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Budgude P, Kale V, Vaidya A. Microvesicles and exosomes isolated from murine bone marrow-derived mesenchymal stromal cells primed with p38MAPK inhibitor differentially regulate hematopoietic stem cell function. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2025; 53:122-137. [PMID: 40062630 DOI: 10.1080/21691401.2025.2475095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 01/07/2025] [Accepted: 02/27/2025] [Indexed: 05/13/2025]
Abstract
The signaling mechanisms active within mesenchymal stromal cells (MSCs) influence the composition of microvesicles (MVs) and exosomes (Exos) secreted by them. Previously, we showed that priming MSCs with a p38 pharmacological inhibitor (pMSCs) rejuvenates them and improves their ability to promote ex vivo hematopoietic stem cell (HSC) expansion. This study examined whether pMSCs exerted HSC-supportive ability via MVs (pMVs) and Exos (pExos). Our findings demonstrate distinct regulation of HSC fate by pMVs and pExos. pMVs promoted the expansion of long-term HSCs (LT-HSCs), distinguished by their robust self-renewal capacity and superior engraftment ability. In contrast, pExos facilitated expansion of short-term HSCs (ST-HSCs) with high proliferative and differentiation potential. Infusing a combination of pMVs- and pExos-expanded HSCs as a composite graft resulted in significantly higher HSC engraftment, emphasizing the synergistic interaction between LT- and ST-HSC populations. Gene expression studies, functional and phenotypic experiments showed that pMVs regulate HSC quiescence via the Egr1/Cdkn1a axis, while pExos control HSC proliferation via the Nfya/Cdkn1a axis. These findings provide insights into the molecular mechanisms underlying the differential regulation of HSC function by pMVs and pExos. It also proposes a composite graft strategy of using pMVs and pExos as "MSC-derived biologics" for improving the HSC transplantation success.
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Affiliation(s)
- Pallavi Budgude
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, India
| | - Vaijayanti Kale
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, India
| | - Anuradha Vaidya
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, India
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2
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He F, Guan W. The role of miR-21 as a biomarker and therapeutic target in cardiovascular disease. Clin Chim Acta 2025; 574:120304. [PMID: 40220984 DOI: 10.1016/j.cca.2025.120304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 04/09/2025] [Accepted: 04/09/2025] [Indexed: 04/14/2025]
Abstract
Cardiovascular diseases (CVDs) are the leading causes of death worldwide, accounting for a significant burden on global health systems. The complexity of CVDs arises from their multifactorial etiology, including genetic, environmental, and lifestyle factors. Early diagnosis and effective treatment remain critical for reducing mortality and improving patient outcomes, yet conventional methods often fall short in providing precise, timely information for disease management. MicroRNAs are small non-coding RNAs that regulate gene expression and play pivotal roles in various biological processes, including cardiovascular health. Among them, miR-21 has garnered significant attention due to its involvement in cardiac remodeling, fibrosis, inflammation, and hypertrophy. Elevated levels of miR-21 are frequently observed in conditions such as myocardial infarction, heart failure, and coronary artery disease, positioning it as a potential biomarker for early detection and disease progression. Furthermore, therapeutic strategies targeting miR-21, such as antagomirs and innovative delivery systems, have shown promise in preclinical studies, though challenges like off-target effects and delivery inefficiencies persist. This review aims to provide a comprehensive understanding of miR-21's role in CVDs, addressing its potential as a diagnostic biomarker and therapeutic target. We discuss recent advancements, limitations, and future prospects in miR-21 research, emphasizing the importance of integrating this knowledge into clinical practice to improve CVD management.
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Affiliation(s)
- Fanlong He
- Department of Cardiovascular, Hangzhou Linping District Integrated Traditional Chinese and Western Medicine Hospital, Hangzhou 311100, China
| | - Wenqing Guan
- Department of Public Health, Hangzhou Linping District Integrated Traditional Chinese and Western Medicine Hospital, Hangzhou 311100, China.
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3
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Chen L, Liu Y, Yu C, Cao P, Ma Y, Geng Y, Cai Y, Zhang Y, Liu J, Li Y, Luan Q. Induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) inhibit M1 macrophage polarization and reduce alveolar bone loss associated with periodontitis. Stem Cell Res Ther 2025; 16:223. [PMID: 40317064 PMCID: PMC12046914 DOI: 10.1186/s13287-025-04327-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/09/2025] [Indexed: 05/04/2025] Open
Abstract
BACKGROUND Periodontitis is a chronic inflammatory disease and macrophages play a pivotal role in the progression of periodontitis. Mesenchymal stem cells (MSCs) have emerged as potential therapeutic agents for the treatment of periodontitis due to their immunomodulatory properties and capacity for tissue regeneration. Compared to conventionally derived MSCs, induced pluripotent stem cell-derived MSCs (iMSCs) offer distinct advantages as promising candidates for MSC-based therapies, owing to their non-invasive acquisition methods and virtually unlimited availability. This study aims to investigate the effects and mechanisms of iMSCs in modulating macrophage polarization and alleviating periodontitis-related alveolar bone loss. METHODS iMSCs were generated from iPSCs and characterized for differentiation potential. The effects of iMSCs on macrophage polarization were evaluated using THP-1-derived macrophages under inflammatory conditions (LPS and IFN-γ stimulation). Co-culture assays, cytokine analysis, reactive oxygen species (ROS) detection, transcriptomic analysis, flow cytometry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blot analysis were performed to elucidate the underlying mechanisms. The therapeutic potential of iMSCs was assessed in a ligature-induced periodontitis mouse model using micro-CT, histological analysis, and immunofluorescence staining. RESULTS iMSCs inhibit M1 macrophage polarization through the suppression of the NF-κB signaling pathway. Additionally, iMSCs reduce the production of pro-inflammatory cytokines (IL-1β, IL-17) and reactive oxygen species (ROS), while enhancing the secretion of anti-inflammatory cytokines (IL-10) and growth factors (VEGF), thereby improving the inflammatory microenvironment. Under inflammatory conditions, iMSCs preserve the osteogenic potential of periodontal ligament stem cells (PDLSCs) and alleviate alveolar bone loss in mice with periodontitis. In vivo, iMSCs reduce the number of M1 macrophages and inhibit the activation of NF-κB in periodontal tissues, supporting their anti-inflammatory and immunomodulatory effects. CONCLUSION iMSCs demonstrate significant therapeutic potential in periodontitis by modulating macrophage polarization, reducing oxidative stress, and mitigating alveolar bone loss associated with the disease. These findings provide new insights into the mechanisms of iMSCs and their application as cell-based therapies for periodontal diseases.
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Affiliation(s)
- Liang Chen
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Yuanqing Liu
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Chenhao Yu
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Pei Cao
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Yiming Ma
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Yiran Geng
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Yu Cai
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Yong Zhang
- First Clinical Division, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Jia Liu
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China
| | - Yang Li
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University, Beijing, People's Republic of China.
| | - Qingxian Luan
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, People's Republic of China.
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Qayyum AA, Lund TK, Jensen PB, Jensen K, Haack-Sørensen M, Ekblond A, Nørgaard MJ, Møller-Sørensen H, Mathiasen AB, Møller CH, Rørvig SB, Kalhauge A, Bruunsgaard H, Litman T, Johansen EM, Højgaard LD, Kastrup J, Perch M. Allogeneic mesenchymal stromal cell therapy on primary graft dysfunction after lung transplantation. JHLT OPEN 2025; 8:100254. [PMID: 40247997 PMCID: PMC12005341 DOI: 10.1016/j.jhlto.2025.100254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/19/2025]
Abstract
Background Primary graft dysfunction (PGD) is common in lung transplantation affecting 15-30% of recipients. It represents a multifactorial injury to the transplanted lung within the first 72 hours after transplantation.We aimed to investigate clinical safety and efficacy of allogeneic adipose tissue-derived stromal cells (ASCs), as an add-on therapy in patients undergoing double lung transplantation. Methods Single center, double-blinded, investigator-initiated randomized phase I/II study with intravenous infusion of either ASCs or placebo within two hours after lung transplantation. A total of 31 patients were included and randomized 1:1:1 to either 200 million or 100 million ASCs, or placebo infusion.The primary endpoint was difference in PGD grade 72 hours after transplantation between groups. Results No significant differences in PGD were seen between the 3 groups 72 hours after lung transplantation (P=0.426). Combined ASC groups compared to placebo group did not show any difference in PGD 72 hours after transplantation (P=0.252). A reduced progression in PGD from day 1 to day 3 and day 2 to day 3 was observed between the ASC treated patients and patients in the placebo group (P=0.034 and P=0.034, respectively). There were no significant differences in number of serious adverse events or in secondary endpoints such as kidney function, lung function, or quality-of-life between groups. Conclusions Intravenous infusion of allogeneic ASCs in patients immediately after double lung transplantation was safe. The therapy did not show statistic difference in PGD between groups 72 hours after lung transplantation. Clinical trial registration information EudraCT number 2019-004848-30 and NCT04714801.
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Affiliation(s)
- Abbas Ali Qayyum
- Cardiology Stem Cell Centre, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Cardiology, Hvidovre hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Kromann Lund
- Department of Cardiology, Section for Lung Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Pia Bredahl Jensen
- Department of Cardiothoracic Anaesthesiology and Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Kristine Jensen
- Department of Cardiology, Section for Lung Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Mandana Haack-Sørensen
- Cardiology Stem Cell Centre, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Cell2Cure Aps, Birkerød, Denmark
| | - Annette Ekblond
- Cardiology Stem Cell Centre, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Cell2Cure Aps, Birkerød, Denmark
| | - Morten Juhl Nørgaard
- Cardiology Stem Cell Centre, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Hasse Møller-Sørensen
- Department of Cardiothoracic Anaesthesiology and Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Anders Bruun Mathiasen
- Cardiology Stem Cell Centre, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Christian Holdflod Møller
- Department of Cardio-thoracic surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Sara Bird Rørvig
- Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Anna Kalhauge
- Department of Radiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Helle Bruunsgaard
- Department of Clinical immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Litman
- Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
| | - Ellen Mønsted Johansen
- Cardiology Stem Cell Centre, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lisbeth Drozd Højgaard
- Cardiology Stem Cell Centre, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jens Kastrup
- Cardiology Stem Cell Centre, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Cell2Cure Aps, Birkerød, Denmark
| | - Michael Perch
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Cardiology, Section for Lung Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Wang LT, Wang HH, Jiang SS, Chang CC, Hsu PJ, Liu KJ, Sytwu HK, Yen BL, Yen ML. Lack of IFN-γ response of human uterine myometrium-derived MSCs significantly improve multiple IBD parameters compared to bone marrow MSCs: Implications for anti-TNFα-refractory patients. Pharmacol Res 2025; 215:107716. [PMID: 40154933 DOI: 10.1016/j.phrs.2025.107716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/24/2025] [Accepted: 03/25/2025] [Indexed: 04/01/2025]
Abstract
The clinical efficacy of mesenchymal stem cell (MSC) therapy for inflammatory bowel disease (IBD) is inconsistent and often fails to match promising preclinical findings. To improve outcome, we compared MSCs isolated from human uterine myometrium (Ut), a readily-available tissue source from a unique immune niche, to bone marrow (BM) MSCs, the most common source, in a murine IBD model with mechanisms underlying differential effects. In this study, human BMMSCs and UtMSCs were intravenously administered to mice with dextran sulfate sodium-induced colitis and evaluated for disease activity, microbiome composition, and cellular immunity. Bioinformatics analyses including patient data were performed to further specify involved mechanisms with subsequent functional validation performed. We found that UtMSC but not BMMSC treatment significantly reversed disease parameters by improving microbiome and reducing mesenteric lymph node IFN-γ and IL-17A-secreting T cells. Transcriptomic analysis revealed UtMSCs had reduced MHC II pathway activation compared to BMMSCs. Functional validation confirmed UtMSCs compared to BMMSCs expressed lower IFN-γ receptors, prevent MHC II-mediated human unstimulated T cell activation, and modulated stimulated T helper (Th) cells away from effector phenotypes while increasing regulatory T cells (Tregs) and IL-10 levels. Bioinformatics from IBD patients resistant to non-T cell-specific therapies implicated persistent MHC II-mediated Th1/Th17 activation as key drivers of disease. Overall, UtMSCs outperformed BMMSCs in improving microbiota, avoiding IFN-γ responses, and modulating overall Th responses, suggesting this MSC source may offer more significant effectiveness for IBD and Th1/Th17-mediated conditions. Our findings also highlight that understanding MSC source-specific therapeutic mechanisms is crucial for optimizing clinical therapies.
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Affiliation(s)
- Li-Tzu Wang
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan; School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Hsiu-Huan Wang
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan, Taiwan
| | | | - Chia-Chih Chang
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan, Taiwan
| | - Pei-Ju Hsu
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan, Taiwan
| | - Ko-Jiunn Liu
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; National Institute of Cancer Research, NHRI, Tainan, Taiwan
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases & Vaccinology, NHRI, Zhunan, Taiwan; Graduate Institute of Microbiology & Immunology, National Defense Medical Center, Taipei, Taiwan
| | - B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan, Taiwan; Department of Obstetrics & Gynecology, Cathay General Hospital Shiji, New Taipei, Taiwan.
| | - Men-Luh Yen
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan.
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Weeratunga P, Harman RM, Jager MC, Van de Walle GR. Footprint-free induced pluripotent stem cells can be successfully differentiated into mesenchymal stromal cells in the feline model. Stem Cell Res Ther 2025; 16:195. [PMID: 40254569 PMCID: PMC12010622 DOI: 10.1186/s13287-025-04325-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 04/09/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Induced pluripotent stem cells (iPSCs) can propagate indefinitely and give rise to every other cell type, rendering them invaluable for disease modelling, drug development research, and usage in regenerative medicine. While feline iPSCs have been described, there are currently no reports on generating genome integration (footprint)-free iPSCs from domestic cats. Therefore, the objective of this study was to generate feline iPSCs from fetal fibroblasts using non-integrative Sendai virus (SeV) vectors carrying human transcription factors. Moreover, these iPSCs were differentiated into mesenchymal stromal cells (MSCs), which can be used as an alternative to tissue-derived MSCs. METHODS Feline fetal fibroblasts were transduced with CytoTune-iPS 2.0 Sendai Reprogramming vectors at recommended multiplicity of infections (MOI) and cultured for about 6 days. At 7 days post transduction cells were dissociated, replated on inactivated feeder cells and maintained in iPSC medium for 28 days with daily medium change. Emerging iPSC colonies were mechanically passaged and transferred to fresh feeder cells and further passaged every 6-8 days. Four feline iPSC lines were generated, with two selected for further in-depth characterization. Feline iPSCs were then differentiated into MSCs using a serial plating strategy and an inhibitor of the transforming growth factor-β (TGF-β) type I receptor. RESULTS Feline iPSCs exhibited characteristic colony morphology, high nuclear-to-cytoplasmic ratio, positive alkaline phosphatase activity, and expressed feline OCT4, SOX2, and Nanog homeobox (NANOG) stem cell markers. Expression of SeV-derived transgenes decreased during passaging to be eventually lost from the host cells and feline iPSCs could be stably maintained for over 35 passages. Feline iPSCs differentiated into embryoid bodies in vitro and did not form fully differentiated teratomas; instead, they generated in vivo masses containing mesodermal tissue derivatives when injected into immunodeficient mice. Feline iPSC-derived MSCs were plastic adherent, displayed MSC-like morphology, expressed MSC-specific surface markers, and differentiated into cells from the mesodermal lineage in vitro. RNA deep sequencing identified 1,189 differentially expressed genes in feline iPSC-derived MSCs compared to feline iPSCs. CONCLUSION We demonstrated the generation of footprint-free iPSCs from domestic cats and their directed differentiation potential towards MSCs. These SeV-derived feline iPSCs and iPSC-derived MSCs will provide valuable models to study feline diseases and explore novel therapeutic strategies and can serve as translational models for human health, leading to increased knowledge on disease pathogenesis and improved therapeutic interventions.
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Affiliation(s)
- Prasanna Weeratunga
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 235 Hungerford Hill Road, Ithaca, NY, 14850, USA
| | - Rebecca M Harman
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 235 Hungerford Hill Road, Ithaca, NY, 14850, USA
| | - Mason C Jager
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Gerlinde R Van de Walle
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 235 Hungerford Hill Road, Ithaca, NY, 14850, USA.
- Department of Veterinary Pathobiology, The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Edinburgh, UK.
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Nie J, Zhou L, Tian W, Liu X, Yang L, Yang X, Zhang Y, Wei S, Wang DW, Wei J. Deep insight into cytokine storm: from pathogenesis to treatment. Signal Transduct Target Ther 2025; 10:112. [PMID: 40234407 PMCID: PMC12000524 DOI: 10.1038/s41392-025-02178-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 12/22/2024] [Accepted: 02/12/2025] [Indexed: 04/17/2025] Open
Abstract
Cytokine storm (CS) is a severe systemic inflammatory syndrome characterized by the excessive activation of immune cells and a significant increase in circulating levels of cytokines. This pathological process is implicated in the development of life-threatening conditions such as fulminant myocarditis (FM), acute respiratory distress syndrome (ARDS), primary or secondary hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome (CRS) associated with chimeric antigen receptor-modified T (CAR-T) therapy, and grade III to IV acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. The significant involvement of the JAK-STAT pathway, Toll-like receptors, neutrophil extracellular traps, NLRP3 inflammasome, and other signaling pathways has been recognized in the pathogenesis of CS. Therapies targeting these pathways have been developed or are currently being investigated. While novel drugs have demonstrated promising therapeutic efficacy in mitigating CS, the overall mortality rate of CS resulting from underlying diseases remains high. In the clinical setting, the management of CS typically necessitates a multidisciplinary team strategy encompassing the removal of abnormal inflammatory or immune system activation, the preservation of vital organ function, the treatment of the underlying disease, and the provision of life supportive therapy. This review provides a comprehensive overview of the key signaling pathways and associated cytokines implicated in CS, elucidates the impact of dysregulated immune cell activation, and delineates the resultant organ injury associated with CS. In addition, we offer insights and current literature on the management of CS in cases of FM, ARDS, systemic inflammatory response syndrome, treatment-induced CRS, HLH, and other related conditions.
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Grants
- 82070217, 81873427 National Natural Science Foundation of China (National Science Foundation of China)
- 82100401 National Natural Science Foundation of China (National Science Foundation of China)
- 81772477, 81201848, 82473220 National Natural Science Foundation of China (National Science Foundation of China)
- 82330010,81630010,81790624 National Natural Science Foundation of China (National Science Foundation of China)
- National High Technology Research and Development Program of China, Grant number: 2021YFA1101500.
- The Hubei Provincial Natural Science Foundation (No.2024AFB050)
- Project of Shanxi Bethune Hospital, Grant Numbber: 2023xg02); Fundamental Research Program of Shanxi Province, Grant Numbber: 202303021211224
- The Key Scientific Research Project of COVID-19 Infection Emergency Treatment of Shanxi Bethune Hospital (2023xg01), 2023 COVID-19 Research Project of Shanxi Provincial Health Commission (No.2023XG001, No. 2023XG005), Four “Batches” Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province (2023XM003), Cancer special Fund research project of Shanxi Bethune Hospital (No. 2020-ZL04), and External Expert Workshop Fund Program of Shanxi Provincial Health Commission(Proteomics Shanxi studio for Huanghe professor)
- Fundamental Research Program of Shanxi Province(No.202303021221192); 2023 COVID-19 Emergency Project of Shanxi Health Commission (Nos.2023XG001,2023XG005)
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Affiliation(s)
- Jiali Nie
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Ling Zhou
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Branch of National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Tuberculosis Prevention and Control Institute), Wuhan, China
| | - Weiwei Tian
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Xiansheng Liu
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Branch of National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Tuberculosis Prevention and Control Institute), Wuhan, China
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Liping Yang
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Xingcheng Yang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yicheng Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuang Wei
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Branch of National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Tuberculosis Prevention and Control Institute), Wuhan, China.
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China.
| | - Jia Wei
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Kwon J(E, Kang C, Moghtader A, Shahjahan S, Bibak Bejandi Z, Alzein A, Djalilian AR. Emerging Treatments for Persistent Corneal Epithelial Defects. Vision (Basel) 2025; 9:26. [PMID: 40265394 PMCID: PMC12015846 DOI: 10.3390/vision9020026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/16/2025] [Accepted: 03/27/2025] [Indexed: 04/24/2025] Open
Abstract
Persistent corneal epithelial defects (PCEDs) are a challenging ocular condition characterized by the failure of complete corneal epithelial healing after an insult or injury, even after 14 days of standard care. There is a lack of therapeutics that target this condition and encourage re-epithelialization of the corneal surface in a timely and efficient manner. This review aims to provide an overview of current standards of management for PCEDs, highlighting novel, emerging treatments in this field. While many of the current non-surgical treatments aim to provide lubrication and mechanical support, novel non-surgical approaches are undergoing development to harness the proliferative and healing properties of human mesenchymal stem cells, platelets, lufepirsen, hyaluronic acid, thymosin ß4, p-derived peptide, and insulin-like growth factor for the treatment of PCEDs. Novel surgical treatments focus on corneal neurotization and limbal cell reconstruction using novel scaffold materials and cell-sources. This review provides insights into future PCED treatments that build upon current management guidelines.
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Affiliation(s)
- Jeonghyun (Esther) Kwon
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (J.K.); (A.M.); (S.S.); (Z.B.B.); (A.A.)
| | - Christie Kang
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA;
| | - Amirhossein Moghtader
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (J.K.); (A.M.); (S.S.); (Z.B.B.); (A.A.)
| | - Sumaiya Shahjahan
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (J.K.); (A.M.); (S.S.); (Z.B.B.); (A.A.)
| | - Zahra Bibak Bejandi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (J.K.); (A.M.); (S.S.); (Z.B.B.); (A.A.)
| | - Ahmad Alzein
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (J.K.); (A.M.); (S.S.); (Z.B.B.); (A.A.)
| | - Ali R. Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (J.K.); (A.M.); (S.S.); (Z.B.B.); (A.A.)
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Wang LT, Juang SE, Lan CL, Chang HH, He AC, Chen WA, Huang YW, Van Dyke TE, Chen YW, Ma KSK. Titanium implants trigger extra-periodontal T cell-mediated immunity. Biomater Sci 2025; 13:1543-1553. [PMID: 39957356 DOI: 10.1039/d4bm00246f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2025]
Abstract
Peri-implant inflammation and periodontitis share a common etiology rooted in periodontopathic bacterial invasion, with periodontitis notably linked to systemic inflammatory comorbidities involving T cells. However, the intricate processes within the peri-implant microenvironment and systemic repercussions of implants, particularly related to implant materials, remain inadequately understood. We aim to elucidate the impact of contact with titanium materials, widely employed in dental implants for their high biocompatibility and excellent corrosion resistance, on diverse T cell subpopulations. This study adopts a comprehensive approach, encompassing (1) transcriptomic profiling of peri-implant epithelium in a rat model, (2) examination of phenotypic and functional changes in T cell immunity in human blood cells cultured on titanium discs, and (3) in vivo validation of T cells in implanted mice. Transcriptomic evidence and functional in vitro results revealed that exposure to titanium materials promoted T cell activation and differentiation towards inflammatory subsets, and escalated the secretion of corresponding cytokines. In vivo results showed that most of the gingiva-extracted T cells were activated in both healthy and implanted mice, the latter exhibiting significant lymphadenitis. High-dimensional flow cytometric findings in the in vivo lymphadenitis model indicated titanium-induced T cell immunity, involving preferential activation of Th1, Th17, and Tc1 cells over Tregs in adjacent lymph nodes within three days after implant placement. These findings highlight the pivotal role of T cells in the initiation of peri-implant inflammation, emphasizing the need to understand extra-periodontal inflammatory complications associated with implant surgeries. Our study provides a foundation for future therapeutic strategies targeting T cell responses to enhance the success and longevity of dental implant treatments.
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Affiliation(s)
- Li-Tzu Wang
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Sin-Ei Juang
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan
| | - Chi-Lun Lan
- Department of Dentistry, National Taiwan University Hospital & Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
| | - Hsuan-Hao Chang
- Department of Dentistry, National Taiwan University Hospital & Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
| | - Ai-Chia He
- Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan
| | - Wei-An Chen
- Department of Dentistry, National Taiwan University Hospital & Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
| | - Yu-Wen Huang
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Thomas E Van Dyke
- Center for Clinical and Translational Research, ADA Forsyth Institute, Cambridge, Massachusetts, USA.
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA
| | - Yi-Wen Chen
- Department of Dentistry, National Taiwan University Hospital & Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
- Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan
| | - Kevin Sheng-Kai Ma
- Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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10
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Narvekar S, Baliga SD, Angadi PV. Dental pulp stem cells as a novel antifibrotic therapy for oral submucous fibrosis: An in vitro study. J Oral Biol Craniofac Res 2025; 15:383-389. [PMID: 40034371 PMCID: PMC11872489 DOI: 10.1016/j.jobcr.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/02/2025] [Accepted: 02/04/2025] [Indexed: 03/05/2025] Open
Abstract
Background Oral submucous fibrosis (OSMF) is a chronic, potentially malignant disorder associated with areca nut consumption. It is characterized by progressive fibrosis, trismus, and a significant risk of malignancy, with limited treatment options primarily offering symptomatic relief. Dental pulp stem cells (DPSCs), a type of mesenchymal stem cells (MSCs), have shown potential for modulating fibrotic conditions through their immunomodulatory and regenerative properties. This study evaluates the antifibrotic potential of DPSCs on OSMF fibroblasts in an in vitro model. Methods DPSCs were isolated from healthy permanent teeth and characterized using flow cytometry for MSC markers (CD73, CD90, CD44, CD105). Fibroblasts were cultured from OSMF biopsy samples and validated through magnetic sorting and morphological analysis. The antifibrotic effects of DPSCs on fibroblasts were evaluated using assays for collagen gel contraction, proliferation, TGF-β1 secretion, and morphological changes. Data were analyzed for statistical significance using appropriate tests. Results The mean collagen gel size decreased from 3.235 mm (95 % CI: 1.65-4.82 mm) in the control group to 1.00 mm (95 % CI: -0.27 - 2.27 mm) in the DPSC-treated group. Fibroblast viability declined significantly over 72 h (p < 0.05). TGF-β1 secretion was markedly lower in DPSC-treated fibroblasts (339.38 pg/mL vs 637.61 pg/mL, p = 0.000393, Cohen's d = 19.15). Conclusion DPSCs exhibit strong antifibrotic properties by inhibiting collagen contraction, suppressing fibroblast proliferation, and reducing TGF-β1 secretion. These findings suggest DPSCs as a promising cell-based therapy for OSMF. Further in vivo studies are warranted for clinical translation. Trial registration number Not applicable.
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Affiliation(s)
- Snehalata Narvekar
- Department of Oral and Maxillofacial Surgery,KLE V K Institute of Dental Sciences, K LE Academy of Higher Education and Research, Belagavi, India
| | - Shridhar D. Baliga
- Department of Oral and Maxillofacial Surgery, KLE V K Institute of Dental Sciences, KLE Academy of Higher Education and Research, Belagavi, India
| | - Punnya V Angadi
- Department of Oral and Maxillofacial Pathology and Microbiology, KLE V K Institute of Dental Sciences, KLE Academy of Higher Education and Research, Belagavi, India
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11
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Che H, Hart ML, Lauer JC, Selig M, Voelker M, Kurz B, Rolauffs B. A xenogenic-free culture medium for cell micro-patterning systems as cell-instructive biomaterials for potential clinical applications. Biomed Mater 2025; 20:025008. [PMID: 39719129 DOI: 10.1088/1748-605x/ada335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 12/24/2024] [Indexed: 12/26/2024]
Abstract
Cell micro-patterning controls cell fate and function and has potential for generating therapeutically usable mesenchymal stromal cell (MSC) populations with precise functions. However, to date, the micro-patterning of human cells in a translational context has been impossible because only ruminant media supplements, e.g. fetal bovine serum (FBS), are established for use with micro-patterns (MPs). Thus, there are currently no good manufacturing practice (GMP)-compliant media available for MPs. This study tested a xenogenic-free human plasma and platelet lysate (hP + PL) medium supplement to determine its compatibility with MPs. Unfiltered hP + PL medium resulted in significant protein deposition, creating a 'carpet-like' layer that rendered MPs ineffective. Filtration (3×/5×) eliminated this effect. Importantly, quantitative comparison using droplet digital PCR revealed that human MSCs in all media types exhibited similar profiles with strong myogenic Calponin 1/Transgelin 2 (TAGLN2) and weaker osteogenic alkaline phosphatase/Runt-related transcription factor 2 marker expression, and much weaker adipogenic (lipoprotein lipase/peroxisome proliferator-activated receptor gamma) and chondrogenic (collagen type II/aggrecan) expression, with profiles being dominated by myogenic markers. Within these similar profiles, an even stronger induction of the myogenic marker TAGLN2 by all hP + PL- compared to FBS-containing media. Overall, this suggested that FBS can be replaced with hP + PL without altering differentiation profiles. However, assessing individual MSC responses to various MP types with defined categories revealed that unfiltered hP + PL medium was unusable. Importantly, FBS- and 3× filtered hP + PL media were comparable in each differentiation category. Summarized, this study recommends 3× filtered hP + PL as a xenogenic-free and potentially GMP-compliant alternative to FBS as a culture medium supplement for micro-patterning cell populations in both basic and translational research that will ensure consistent and reliable MSC micro-patterning for therapeutic use.
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Affiliation(s)
- Hui Che
- Orthopedics and Sports Medicine Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, People's Republic of China
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79108 Freiburg im Breisgau, Germany
| | - Melanie L Hart
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79108 Freiburg im Breisgau, Germany
| | - Jasmin C Lauer
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79108 Freiburg im Breisgau, Germany
| | - Mischa Selig
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79108 Freiburg im Breisgau, Germany
| | - Marita Voelker
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79108 Freiburg im Breisgau, Germany
| | - Bodo Kurz
- Department of Anatomy, Christian-Albrechts-University, Otto-Hahn-Platz 8, 24118 Kiel, Germany
| | - Bernd Rolauffs
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79108 Freiburg im Breisgau, Germany
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12
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Huang WC, Li YC, Chen PX, Ma KSK, Wang LT. Mesenchymal stem cell therapy as a game-changer in liver diseases: review of current clinical trials. Stem Cell Res Ther 2025; 16:3. [PMID: 39762946 PMCID: PMC11705688 DOI: 10.1186/s13287-024-04127-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 12/21/2024] [Indexed: 01/11/2025] Open
Abstract
Chronic liver diseases, including cirrhosis and liver failure, remain formidable challenges due to their complex progression and limited therapeutic options. Mesenchymal stem cell (MSC) therapy has emerged as a game-changing approach, leveraging its potent immunomodulatory, anti-fibrotic, and regenerative capabilities, along with the ability to transdifferentiate into hepatocytes. This review delves into the latest advances in MSC-based treatments for chronic and end-stage liver diseases, as highlighted in current clinical trials. MSCs derived from bone marrow and umbilical cord have shown remarkable promise in reversing liver damage, improving liver function, and providing hope for patients who do not respond to conventional therapies. When administered through hepatic, portal, or peripheral veins, MSCs have significantly improved liver histology, reduced fibrosis, and restored functional capacity. Furthermore, MSC-derived materials, such as extracellular vesicles and exosomes, are emerging as cutting-edge tools for treating liver failure and mitigating post-transplant complications. While autologous MSC-derived hepatocytes hold promise for non-fatal cirrhosis, allogeneic MSCs are being applied in more severe conditions, including liver failure and transplantation cases. Despite these promising early outcomes, larger trials and long-term studies are essential to fully harness MSCs as a transformative, off-the-shelf alternative to liver transplantation, heralding a new era in regenerative liver therapies.
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Affiliation(s)
- Wei-Chen Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Laboratory of Clinical Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Yuan-Chi Li
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan
| | - Pin-Xuan Chen
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan
| | - Kevin Sheng-Kai Ma
- Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Li-Tzu Wang
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan.
- Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
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13
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Hemati S, Ghiasi M, Salimi A. Osteogenic Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells on Composite Polymeric Scaffolds: A Review. Curr Stem Cell Res Ther 2025; 20:33-49. [PMID: 38315659 DOI: 10.2174/011574888x263333231218065453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 02/07/2024]
Abstract
The mesenchymal stem cells (MSCs) are the fundamental part of bone tissue engineering for the emergence of reconstructive medicine. Bone tissue engineering has recently been considered a promising strategy for treating bone diseases and disorders. The technique needs a scaffold to provide an environment for cell attachment to maintain cell function and a rich source of stem cells combined with appropriate growth factors. MSCs can be isolated from adipose tissue (ASCs), bone marrow (BM-MSCs), or umbilical cord (UC-MSCs). In the present study, the potential of ASCs to stimulate bone formation in composite polymeric scaffolds was discussed and it showed that ASCs have osteogenic ability in vitro. The results also indicated that the ASCs have the potential for rapid growth, easier adipose tissue harvesting with fewer donor site complications and high proliferative capacity. The osteogenic differentiation capacity of ASCs varies due to the culture medium and the addition of factors that can change signaling pathways to increase bone differentiation. Furthermore, gene expression analysis has a significant impact on improving our understanding of the molecular pathways involved in ASCs and, thus, osteogenic differentiation. Adding some drugs, such as dexamethasone, to the biomaterial composite also increases the formation of osteocytes. Combining ASCs with scaffolds synthesized from natural and synthetic polymers seems to be an effective strategy for bone regeneration. Applying exopolysaccharides, such as schizophyllan, chitosan, gelatin, and alginate in composite scaffolds enhances the osteogenesis potential of ASCs in bone tissue regeneration.
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Affiliation(s)
- Saideh Hemati
- Department of Cellular and Molecular Biology, Faculty of Biology, Science and Research Branch of Islamic Azad University, Tehran, Iran
| | - Mohsen Ghiasi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Salimi
- Tissue Engineering and Regenerative Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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14
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Aisanjiang M, Dai W, Wu L, Yuan Y, Liu S, Liao G, Li L, Tong X, Zhang H, Chen Y, Liu J, Cheng J, Wang C, Lu Y. Ameliorating lung fibrosis and pulmonary function in diabetic mice: Therapeutic potential of mesenchymal stem cell. Biochem Biophys Res Commun 2024; 737:150495. [PMID: 39126861 DOI: 10.1016/j.bbrc.2024.150495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 07/27/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024]
Abstract
This study aimed to investigate the potential of mesenchymal stem cells (MSCs) in alleviating diabetic lung injury by decreasing inflammation, fibrosis and recovering tissue macrophage homeostasis. To induce pulmonary injuries in an in vivo murine model, we utilized a streptozotocin (STZ), and high-fat diet (HFD) induced diabetic C57 mouse model. Subsequently, human umbilical cord-derived MSCs (hUC-MSCs) were administered through the tail vein on a weekly basis for a duration of 4 weeks. In addition, in vitro experiments involved co-culturing of isolated primary abdominal macrophages from diabetic mice and high glucose-stimulated MLE-12 cells with hUC-MSCs. The objective was to evaluate if hUC-MSCs co-culturing could effectively mitigate cell inflammation and fibrosis. Following hUC-MSCs injection, diabetic mice displayed enhanced pulmonary functional parameters, reduced pulmonary fibrosis, and diminished inflammation. Notably, the dynamic equilibrium of lung macrophages shifted from the M1 phenotype to the M2 phenotype, accompanied by a notable reduction in various indicators associated with inflammation and fibrosis. Results from cell co-culturing experiments further supported this trend, demonstrating a reduction in inflammatory and fibrotic indicators. In conclusion, our findings suggest that hUC-MSCs treatment holds promise in mitigating diabetic pulmonary injury by significantly reducing inflammation, fibrosis and maintain tissue macrophage homeostasis within the lungs. This study sheds light on the therapeutic potential of hUC-MSCs in managing diabetic complications affecting the pulmonary system.
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Affiliation(s)
- Maikeliya Aisanjiang
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Wenshu Dai
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Luna Wu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yujia Yuan
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Shuyun Liu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Guangneng Liao
- Animal experimental center of West China hospital, Sichuan University, Chengdu, China
| | - Lan Li
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Tong
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Heteng Zhang
- Sichuan Neo-Life Stem Cell Biotech Inc., Chengdu, China
| | - Younan Chen
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Jingping Liu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Jingqiu Cheng
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Chengshi Wang
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, China.
| | - Yanrong Lu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Transplant Engineering and Immunology, NHFPC, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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15
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Sanap A, Joshi K, Kheur S, Bhonde R. Stem cell secretome restore the adipo-osteo differentiation imbalance in diabetic dental pulp-derived mesenchymal stem cells. Chronic Dis Transl Med 2024; 10:340-349. [PMID: 39429485 PMCID: PMC11483546 DOI: 10.1002/cdt3.125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 03/19/2024] [Accepted: 04/16/2024] [Indexed: 10/22/2024] Open
Abstract
Background Mesenchymal stem cells (MSCs) from type 2 diabetes mellitus (T2DM) individuals exhibit increased adipogenesis and decreased osteogenesis. We investigated the potential of adipose tissue-derived MSCs (ADMSCs) secretome obtained from healthy individuals in restoring the tumor necrosis factor-α (TNF-α) mediated imbalance in the adipo/osteogenic differentiation in the dental pulp-derived MSCs obtained from T2DM individuals (dDPMSCs). Methods dDPMSCs were differentiated into adipocytes and osteocytes using a standard cocktail in the presence of (a) induction cocktail, (b) induction cocktail + TNF-α, and (c) induction cocktail+ TNF-α + ADMSCs-secretome (50%) for 15 and 21 days resp. Differentiated adipocytes and osteocytes were stained by oil red O and alizarin red and analyzed by using ImageJ software. Molecular expression of the key genes involved was analyzed by using reverse-transcription polymerase chain reaction (RT-PCR). Results Treatment of TNF-α augmented the adipogenesis (9571 ± 765 vs. 19,815 ± 1585 pixel, p < 0.01) and decreased the osteogenesis (15,603 ± 1248 vs. 11,894 ± 951 pixel, p < 0.05) of dDPMSCs as evidenced by the oil red O and alizarin red staining respectively. Interestingly, dDPMSCs differentiated along with TNF-α and 50% ADMSCs secretome exhibited enhanced osteogenesis (11,894 ± 951 vs. 41,808 ± 3344 pixel, p < 0.01) and decreased adipogenesis (19,815 ± 1585 vs. 4480 ± 358 pixel, p < 0.01). Additionally, dDPMSCs differentiated along with ADMSCs secretome exhibited decreased expression of PPARg (p < 0.01), C/EBPa (p < 0.05), and FAS (p < 0.01) whereas mRNA expression of Runx2 (p < 0.05), Osterix (p < 0.01), and OCN (p < 0.05) was upregulated as revealed by the RT-PCR analysis. Conclusion ADMSCs secretome from healthy individuals restore the TNF-α influenced differentiation fate of dDPMSCs and therefore can be explored for T2DM clinical management in the future.
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Affiliation(s)
- Avinash Sanap
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and HospitalDr. D. Y. Patil Vidyapeeth, PimpriPuneIndia
| | - Kalpana Joshi
- Department of BiotechnologySinhgad College of Engineering affiliated to Savitribai Phule Pune UniversityPuneIndia
| | - Supriya Kheur
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and HospitalDr. D. Y. Patil Vidyapeeth, PimpriPuneIndia
| | - Ramesh Bhonde
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and HospitalDr. D. Y. Patil Vidyapeeth, PimpriPuneIndia
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16
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Gao Q, Cekuc MS, Ergul YS, Pius AK, Shinohara I, Murayama M, Susuki Y, Ma C, Morita M, Chow SKH, Goodman SB. 3D Culture of MSCs for Clinical Application. Bioengineering (Basel) 2024; 11:1199. [PMID: 39768017 PMCID: PMC11726872 DOI: 10.3390/bioengineering11121199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/19/2024] [Accepted: 11/23/2024] [Indexed: 01/16/2025] Open
Abstract
Mesenchymal stem cells (MSCs) play an important role in regenerative medicine and drug discovery due to their multipotential differentiation capabilities and immunomodulatory effects. Compared with traditional 2D cultures of MSCs, 3D cultures of MSCs have emerged as an effective approach to enhance cell viability, proliferation, and functionality, and provide a more relevant physiological environment. Here, we review the therapeutic potential of 3D-cultured MSCs, highlighting their roles in tissue regeneration and repair and drug screening. We further summarize successful cases that apply 3D MSCs in modeling disease states, enabling the identification of novel therapeutic strategies. Despite these promising applications, we discuss challenges that remain in the clinical translation of 3D MSC technologies, including stability, cell heterogeneity, and regulatory issues. We conclude by addressing these obstacles and emphasizing the need for further research to fully exploit the potential of 3D MSCs in clinical practice.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Stuart B. Goodman
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94304, USA; (Q.G.)
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17
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Zhou JP, Peng SS, Xu J, Cheng XW, Wang XH, Tao JL, Dai HW, Cao X. Exploring the therapeutic potential of urine-derived stem cell exosomes in temporomandibular joint osteoarthritis. FASEB J 2024; 38:e23852. [PMID: 39101942 DOI: 10.1096/fj.202400448rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/15/2024] [Accepted: 07/21/2024] [Indexed: 08/06/2024]
Abstract
Temporomandibular joint osteoarthritis (TMJOA) is a degenerative ailment that causes slow cartilage degeneration, aberrant bone remodeling, and persistent discomfort, leading to a considerable reduction in the patient's life quality. Current treatment options for TMJOA have limited efficacy. This investigation aimed to explore a potential strategy for halting or reversing the progression of TMJOA through the utilization of exosomes (EXOs) derived from urine-derived stem cells (USCs). The USC-EXOs were obtained through microfiltration and ultrafiltration techniques, followed by their characterization using particle size analysis, electron microscopy, and immunoblotting. Subsequently, an in vivo model of TMJOA induced by mechanical force was established. To assess the changes in the cartilage of TMJOA treated with USC-EXOs, we performed histology analysis using hematoxylin-eosin staining, immunohistochemistry, and histological scoring. Our findings indicate that the utilization of USC-EXOs yields substantial reductions in TMJOA, while concurrently enhancing the structural integrity and smoothness of the compromised condylar cartilage surface. Additionally, USC-EXOs exhibit inhibitory effects on osteoclastogenic activity within the subchondral bone layer of the condylar cartilage, as well as attenuated apoptosis in the rat TMJ in response to mechanical injury. In conclusion, USC-EXOs hold considerable promise as a potential therapeutic intervention for TMJOA.
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Affiliation(s)
- Jian-Ping Zhou
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Si-Si Peng
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Jie Xu
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Xing-Wang Cheng
- Department of Orthopedic Surgery, Center for Joint Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-Hui Wang
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Jun-Li Tao
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Hong-Wei Dai
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Xin Cao
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
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18
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Lyu Z, Xin M, Oyston DR, Xue T, Kang H, Wang X, Wang Z, Li Q. Cause and consequence of heterogeneity in human mesenchymal stem cells: Challenges in clinical application. Pathol Res Pract 2024; 260:155354. [PMID: 38870711 DOI: 10.1016/j.prp.2024.155354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/25/2024] [Accepted: 05/14/2024] [Indexed: 06/15/2024]
Abstract
Human mesenchymal stem cells (hMSCs) are mesoderm-derived adult stem cells with self-proliferation capacity, pluripotent differentiation potency, and excellent histocompatibility. These advantages make hMSCs a promising tool in clinical application. However, the majority of clinical trials using hMSC therapy for diverse human diseases do not achieve expectations, despite the prospective pre-clinical outcomes in animal models. This is partly attributable to the intrinsic heterogeneity of hMSCs. In this review, the cause of heterogeneity in hMSCs is systematically discussed at multiple levels, including isolation methods, cultural conditions, donor-to-donor variation, tissue sources, intra-tissue subpopulations, etc. Additionally, the effect of hMSCs heterogeneity on the contrary role in tumor progression and immunomodulation is also discussed. The attempts to understand the cellular heterogeneity of hMSCs and its consequences are important in supporting and improving therapeutic strategies for hMSCs.
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Affiliation(s)
- Zhao Lyu
- Department of Clinical Laboratory, Xi'an International Medical Center Hospital, Xi'an, Shaanxi, China
| | - Miaomiao Xin
- Assisted Reproductive Center, Women's & Children's Hospital of Northwest, Xi'an, Shaanxi, China; University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, Vodnany, Czech Republic
| | - Dale Reece Oyston
- Department of Evolution, Ecology and Behaviour, University of Liverpool, Liverpool, UK
| | - Tingyu Xue
- Department of Clinical Laboratory, Xi'an International Medical Center Hospital, Xi'an, Shaanxi, China
| | - Hong Kang
- Department of Clinical Laboratory, Xi'an International Medical Center Hospital, Xi'an, Shaanxi, China
| | - Xiangling Wang
- Department of Clinical Laboratory, Xi'an International Medical Center Hospital, Xi'an, Shaanxi, China
| | - Zheng Wang
- Medical Center of Hematology, the Second Affiliated Hospital, Army Medical University, Chongqing, Sichuan, China.
| | - Qian Li
- Changsha Medical University, Changsha, Hunan, China.
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19
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Lauvrud AT, Giraudo MV, Wiberg R, Wiberg M, Kingham PJ, Brohlin M. The influence of xeno-free culture conditions on the angiogenic and adipogenic differentiation properties of adipose tissue-derived stem cells. Regen Ther 2024; 26:901-910. [PMID: 39822342 PMCID: PMC11736170 DOI: 10.1016/j.reth.2024.09.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/17/2024] [Accepted: 09/25/2024] [Indexed: 01/19/2025] Open
Abstract
Introduction Before performing cell therapy clinical trials, it is important to understand how cells are influenced by different growth conditions and to find optimal xeno-free medium formulations. In this study we have investigated the properties of adipose tissue-derived stem cells (ASCs) cultured under xeno-free conditions. Methods Human lipoaspirate samples were digested to yield the stromal vascular fraction cells which were then seeded in i) Minimum Essential Medium-α (MEM-α) supplemented with 10 % (v/v) fetal bovine serum (FBS), ii) MEM-α supplemented with 2 % (v/v) human platelet lysate (PLT) or iii) PRIME-XV MSC expansion XSFM xeno-free, serum free medium (XV). Flow cytometry for ASCs markers CD73, CD90 and CD105 together with the putative pericyte marker CD146 was performed. Growth rates were monitored over multiple passages and adipogenic differentiation performed at early and expanded passage culture. Growth factor gene expression was analyzed and an in vitro angiogenesis assay performed. Results Cells in FBS and PLT grew at similar rates whereas the cells cultured in XV medium proliferated significantly faster up to 60 days in culture. All cultures were >98 % positive for CD73, CD90 and CD105, whereas CD146 expression was significantly higher in XV cells. Adipogenic differentiation was most pronounced in cells which had been cultured in XV medium whilst cells grown in PLT were inferior compared with cells from the FBS cultures. IGF1 gene expression was highest in cells cultured in PLT whilst cells grown in XV medium showed 10-fold lower expression compared with FBS cells. In contrast, HGF gene expression was 90-fold greater in cells cultured in XV medium compared with those cultured in FBS. Conditioned medium from XV cultured cells showed the most angiogenic activity, inducing the greatest endothelial cell network formation and maturation. Conclusion Culture under different conditions alters the ASCs characteristics. Since cells cultured in XV medium showed the best adipogenic and angiogenic profile this might be a preferred medium formulation for preparing cells required for reconstructive surgical applications such as cell-assisted fat grafting.
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Affiliation(s)
- Anne Therese Lauvrud
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
- Department of Diagnostics and Intervention, Umeå University, SE-901 87 Umeå, Sweden
| | - Maria Vittoria Giraudo
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
| | - Rebecca Wiberg
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
- Department of Diagnostics and Intervention, Umeå University, SE-901 87 Umeå, Sweden
| | - Mikael Wiberg
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
- Department of Diagnostics and Intervention, Umeå University, SE-901 87 Umeå, Sweden
| | - Paul J. Kingham
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
| | - Maria Brohlin
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
- Department of Clinical Microbiology, Umeå University, SE-901 87 Umeå, Sweden
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20
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Duan H, Tao N, Lv L, Yan KX, You YG, Mao Z, Wang CY, Li X, Jin JY, Wu CT, Wang H. Hepatocyte growth factor enhances the ability of dental pulp stem cells to ameliorate atherosclerosis in apolipoprotein E-knockout mice. World J Stem Cells 2024; 16:575-590. [PMID: 38817328 PMCID: PMC11135256 DOI: 10.4252/wjsc.v16.i5.575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/18/2024] [Accepted: 04/09/2024] [Indexed: 05/24/2024] Open
Abstract
BACKGROUND Atherosclerosis (AS), a chronic inflammatory disease of blood vessels, is a major contributor to cardiovascular disease. Dental pulp stem cells (DPSCs) are capable of exerting immunomodulatory and anti-inflammatory effects by secreting cytokines and exosomes and are widely used to treat autoimmune and inflammation-related diseases. Hepatocyte growth factor (HGF) is a pleiotropic cytokine that plays a key role in many inflammatory and autoimmune diseases. AIM To modify DPSCs with HGF (DPSC-HGF) and evaluate the therapeutic effect of DPSC-HGF on AS using an apolipoprotein E-knockout (ApoE-/-) mouse model and an in vitro cellular model. METHODS ApoE-/- mice were fed with a high-fat diet (HFD) for 12 wk and injected with DPSC-HGF or Ad-Null modified DPSCs (DPSC-Null) through tail vein at weeks 4, 7, and 11, respectively, and the therapeutic efficacy and mechanisms were analyzed by histopathology, flow cytometry, lipid and glucose measurements, real-time reverse transcription polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay at the different time points of the experiment. An in vitro inflammatory cell model was established by using RAW264.7 cells and human aortic endothelial cells (HAOECs), and indirect co-cultured with supernatant of DPSC-Null (DPSC-Null-CM) or DPSC-HGF-CM, and the effect and mechanisms were analyzed by flow cytometry, RT-PCR and western blot. Nuclear factor-κB (NF-κB) activators and inhibitors were also used to validate the related signaling pathways. RESULTS DPSC-Null and DPSC-HGF treatments decreased the area of atherosclerotic plaques and reduced the expression of inflammatory factors, and the percentage of macrophages in the aorta, and DPSC-HGF treatment had more pronounced effects. DPSCs treatment had no effect on serum lipoprotein levels. The FACS results showed that DPSCs treatment reduced the percentages of monocytes, neutrophils, and M1 macrophages in the peripheral blood and spleen. DPSC-Null-CM and DPSC-HGF-CM reduced adhesion molecule expression in tumor necrosis factor-α stimulated HAOECs and regulated M1 polarization and inflammatory factor expression in lipopolysaccharide-induced RAW264.7 cells by inhibiting the NF-κB signaling pathway. CONCLUSION This study suggested that DPSC-HGF could more effectively ameliorate AS in ApoE-/- mice on a HFD, and could be of greater value in stem cell-based treatments for AS.
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Affiliation(s)
- Han Duan
- School of Life Sciences, Hebei University, Baoding 071002, Hebei Province, China
| | - Ning Tao
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Lin Lv
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Kai-Xin Yan
- Department of Cardiology, The Sixth Medical Centre, Chinese People's Liberation Army General Hospital, Beijing 100037, China
| | - Yong-Gang You
- Department of Orthopaedics, The Fourth Medical Centre, Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Zhuang Mao
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Chang-Yao Wang
- School of Life Sciences, Hebei University, Baoding 071002, Hebei Province, China
| | - Xue Li
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Jia-Yan Jin
- Third Cadet Regiment, School of Basic Medical Science, Air Force Medical University, Xi'an 710032, Shaanxi Province, China
| | - Chu-Tse Wu
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Hua Wang
- School of Life Sciences, Hebei University, Baoding 071002, Hebei Province, China
- Beijing Institute of Radiation Medicine, Beijing 100850, China.
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21
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Xu H, Wang B, Li A, Wen J, Su H, Qin D. Mesenchymal Stem Cells-based Cell-free Therapy Targeting Neuroinflammation. Aging Dis 2024; 15:965-976. [PMID: 38722791 PMCID: PMC11081161 DOI: 10.14336/ad.2023.0904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 09/04/2023] [Indexed: 05/13/2024] Open
Abstract
Emerging from several decades of extensive research, key genetic elements and biochemical mechanisms implicated in neuroinflammation have been delineated, contributing substantially to our understanding of neurodegenerative diseases (NDDs). In this minireview, we discuss data predominantly from the past three years, highlighting the pivotal roles and mechanisms of the two principal cell types implicated in neuroinflammation. The review also underscores the extended process of peripheral inflammation that predates symptomatic onset, the critical influence of neuroinflammation, and their dynamic interplay in the pathogenesis of NDDs. Confronting these complex challenges, we introduce compelling evidence supporting the use of mesenchymal stem cell-based cell-free therapy. This therapeutic strategy includes the regulation of microglia and astrocytes, modulation of peripheral nerve cell inflammation, and targeted anti-inflammatory interventions specifically designed for NDDs, while also discussing engineering and safety considerations. This innovative therapeutic approach intricately modulates the immune system across the peripheral and nervous systems, with an emphasis on achieving superior penetration and targeted delivery. The insights offered by this review have significant implications for the better understanding and management of neuroinflammation.
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Affiliation(s)
- Hongjie Xu
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
| | - Bin Wang
- Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China.
| | - Ang Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
| | - Jing Wen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
| | - Huanxing Su
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
| | - Dajiang Qin
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences; Hong Kong SAR, China
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22
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van Griensven M, Balmayor ER. Extracellular vesicles are key players in mesenchymal stem cells' dual potential to regenerate and modulate the immune system. Adv Drug Deliv Rev 2024; 207:115203. [PMID: 38342242 DOI: 10.1016/j.addr.2024.115203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 10/15/2023] [Accepted: 02/05/2024] [Indexed: 02/13/2024]
Abstract
MSCs are used for treatment of inflammatory conditions or for regenerative purposes. MSCs are complete cells and allogenic transplantation is in principle possible, but mostly autologous use is preferred. In recent years, it was discovered that cells secrete extracellular vesicles. These are active budded off vesicles that carry a cargo. The cargo can be miRNA, protein, lipids etc. The extracellular vesicles can be transported through the body and fuse with target cells. Thereby, they influence the phenotype and modulate the disease. The extracellular vesicles have, like the MSCs, immunomodulatory or regenerative capacities. This review will focus on those features of extracellular vesicles and discuss their dual role. Besides the immunomodulation, the regeneration will concentrate on bone, cartilage, tendon, vessels and nerves. Current clinical trials with extracellular vesicles for immunomodulation and regeneration that started in the last five years are highlighted as well. In summary, extracellular vesicles have a great potential as disease modulating entity and treatment. Their dual characteristics need to be taken into account and often are both important for having the best effect.
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Affiliation(s)
- Martijn van Griensven
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, 6229 ER Maastricht, the Netherlands; Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA.
| | - Elizabeth R Balmayor
- Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA; Experimental Orthopaedics and Trauma Surgery, Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
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23
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Karimi F, Nejati B, Rahimi F, Alivirdiloo V, Alipourfard I, Aghighi A, Raji-Amirhasani A, Eslami M, Babaeizad A, Ghazi F, Firouzi Amandi A, Dadashpour M. A State-of-the-Art Review on the Recent Advances of Mesenchymal Stem Cell Therapeutic Application in Systematic Lupus Erythematosus. Immunol Invest 2024; 53:160-184. [PMID: 38031988 DOI: 10.1080/08820139.2023.2289066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with an unknown etiology that has widespread clinical and immunological manifestations. Despite the increase in knowledge about the pathogenesis process and the increase in treatment options, however, the treatments fail in half of the cases. Therefore, there is still a need for research on new therapies. Mesenchymal stem cells (MSCs) are powerful regulators of the immune system and can reduce the symptoms of systemic lupus erythematosus. This study aimed to review the mechanisms of immune system modulation by MSCs and the role of these cells in the treatment of SLE. MSCs suppress T lymphocytes through various mechanisms, including the production of transforming growth factor-beta (TGF-B), prostaglandin E2 (PGE2), nitric oxide (NO), and indolamine 2 and 3-oxygenase (IDO). In addition, MSCs inhibit the production of their autoantibodies by inhibiting the differentiation of lymphocytes. The production of autoantibodies against nuclear antigens is an important feature of SLE. On the other hand, MSCs inhibit antigen delivery by antigen-presenting cells (APCs) to T lymphocytes. Studies in animal models have shown the effectiveness of these cells in treating SLE. However, few studies have been performed on the effectiveness of this treatment in humans. It can be expected that new treatment strategies for SLE will be introduced in the future, given the promising results of MSCs application.
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Affiliation(s)
- Farshid Karimi
- Department of Optometry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Babak Nejati
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Rahimi
- Division of Clinical Laboratory, Zahra Mardani Azar Children Training Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Alivirdiloo
- Medical Doctor Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran
| | - Iraj Alipourfard
- Institute of Physical Chemistry, Polish Academy of Science, Warsaw, Poland
| | - Ali Aghighi
- Department of Clinical Biochemistry, Zahedan University of Medical Science, Zahedan, Iran
| | - Alireza Raji-Amirhasani
- Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Eslami
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Babaeizad
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Farhood Ghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mehdi Dadashpour
- Department of Medical Biotechnology, Semnan University of Medical Sciences, Semnan, Iran
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24
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Yang L, Cao J, Du Y, Zhang X, Hong W, Peng B, Wu J, Weng Q, Wang J, Gao J. Initial IL-10 production dominates the therapy of mesenchymal stem cell scaffold in spinal cord injury. Theranostics 2024; 14:879-891. [PMID: 38169599 PMCID: PMC10758068 DOI: 10.7150/thno.87843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 11/21/2023] [Indexed: 01/05/2024] Open
Abstract
Rationale: Spinal cord injury (SCI) is an acute damage to the central nervous system that results in severe morbidity and permanent disability. Locally implanted scaffold systems with immobilized mesenchymal stem cells (MSCs) have been widely proven to promote locomotor function recovery in SCI rats; however, the underlying mechanism remains elusive. Methods and Results: In this study, we constructed a hyaluronic acid scaffold system (HA-MSC) to accelerate the adhesive growth of human MSCs and prolong their survival time in SCI rat lesions. MSCs regulate local immune responses by upregulating the expression of anti-inflammatory cytokines. Interestingly, the dramatically increased, but transient expression of interleukin 10 (IL-10) is found to be secreted by MSCs in the first week. Blocking the function of the initially produced IL-10 by the antibody completely abolished the neurological and behavioral recovery of SCI rats, indicating a core role of IL-10 in SCI therapy with HA-MSC implantation. Transcriptome analyses indicated that IL-10 selectively promotes the migration and cytokine secretion-associated programs of MSCs, which in turn helps MSCs exert their anti-inflammatory therapeutic effects. Conclusion: Our findings highlight a novel role of IL-10 in regulating MSC migration and cytokine secretion-associated programs, and determine the vital role of IL-10 in the domination of MSC treatment for spinal cord repair.
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Affiliation(s)
- Lijun Yang
- Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jian Cao
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yiwen Du
- Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xunqi Zhang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wenxiang Hong
- Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Bowen Peng
- Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jiahe Wu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qinjie Weng
- Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Jiajia Wang
- Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jianqing Gao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou 310058, China
- Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
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25
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Akerman AW, Alexander KC, Caranasos TG, Ikonomidis JS. Therapeutic potential of mesenchymal stem cells and their secreted extracellular vesicles in thoracic aortic aneurysm disease. J Thorac Cardiovasc Surg 2024; 167:89-93.e1. [PMID: 37084818 PMCID: PMC10882625 DOI: 10.1016/j.jtcvs.2023.03.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/30/2023] [Accepted: 03/31/2023] [Indexed: 04/23/2023]
Affiliation(s)
- Adam W Akerman
- Division of Cardiothoracic Surgery, Department of Surgery, University of North Carolina-Chapel Hill, Chapel Hill, NC
| | - Kyle C Alexander
- Division of Cardiothoracic Surgery, Department of Surgery, University of North Carolina-Chapel Hill, Chapel Hill, NC
| | - Thomas G Caranasos
- Division of Cardiothoracic Surgery, Department of Surgery, University of North Carolina-Chapel Hill, Chapel Hill, NC
| | - John S Ikonomidis
- Division of Cardiothoracic Surgery, Department of Surgery, University of North Carolina-Chapel Hill, Chapel Hill, NC.
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26
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Khalaji A, Mehrtabar S, Jabraeilipour A, Doustar N, Rahmani Youshanlouei H, Tahavvori A, Fattahi P, Alavi SMA, Taha SR, Fazlollahpour-Naghibi A, Shariat Zadeh M. Inhibitory effect of microRNA-21 on pathways and mechanisms involved in cardiac fibrosis development. Ther Adv Cardiovasc Dis 2024; 18:17539447241253134. [PMID: 38819836 PMCID: PMC11143841 DOI: 10.1177/17539447241253134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/18/2024] [Indexed: 06/01/2024] Open
Abstract
Cardiac fibrosis is a pivotal cardiovascular disease (CVD) process and represents a notable health concern worldwide. While the complex mechanisms underlying CVD have been widely investigated, recent research has highlighted microRNA-21's (miR-21) role in cardiac fibrosis pathogenesis. In this narrative review, we explore the molecular interactions, focusing on the role of miR-21 in contributing to cardiac fibrosis. Various signaling pathways, such as the RAAS, TGF-β, IL-6, IL-1, ERK, PI3K-Akt, and PTEN pathways, besides dysregulation in fibroblast activity, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs cause cardiac fibrosis. Besides, miR-21 in growth factor secretion, apoptosis, and endothelial-to-mesenchymal transition play crucial roles. miR-21 capacity regulatory function presents promising insights for cardiac fibrosis. Moreover, this review discusses numerous approaches to control miR-21 expression, including antisense oligonucleotides, anti-miR-21 compounds, and Notch signaling modulation, all novel methods of cardiac fibrosis inhibition. In summary, this narrative review aims to assess the molecular mechanisms of cardiac fibrosis and its essential miR-21 function.
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Affiliation(s)
- Amirreza Khalaji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Mehrtabar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Nadia Doustar
- Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | | | - Amir Tahavvori
- Department of Internal Medicine, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Payam Fattahi
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Seyed Reza Taha
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Andarz Fazlollahpour-Naghibi
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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Li TT, Yao WQ, Dong HB, Wang ZR, Zhang ZY, Yuan MQ, Shi L, Wang FS. Plasma proteomics-based biomarkers for predicting response to mesenchymal stem cell therapy in severe COVID-19. Stem Cell Res Ther 2023; 14:350. [PMID: 38072927 PMCID: PMC10712100 DOI: 10.1186/s13287-023-03573-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 11/16/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND The objective of this study was to identify potential biomarkers for predicting response to MSC therapy by pre-MSC treatment plasma proteomic profile in severe COVID-19 in order to optimize treatment choice. METHODS A total of 58 patients selected from our previous RCT cohort were enrolled in this study. MSC responders (n = 35) were defined as whose resolution of lung consolidation ≥ 51.99% (the median value for resolution of lung consolidation) from pre-MSC to 28 days post-MSC treatment, while non-responders (n = 23) were defined as whose resolution of lung consolidation < 51.99%. Plasma before MSC treatment was detected using data-independent acquisition (DIA) proteomics. Multivariate logistic regression analysis was used to identify pre-MSC treatment plasma proteomic biomarkers that might distinguish between responders and non-responders to MSC therapy. RESULTS In total, 1101 proteins were identified in plasma. Compared with the non-responders, the responders had three upregulated proteins (CSPG2, CTRB1, and OSCAR) and 10 downregulated proteins (ANXA1, AGRG6, CAPG, DDX55, KV133, LEG10, OXSR1, PICAL, PTGDS, and S100A8) in plasma before MSC treatment. Using logistic regression model, lower levels of DDX55, AGRG6, PICAL, and ANXA1 and higher levels of CTRB1 pre-MSC treatment were predictors of responders to MSC therapy, with AUC of the ROC at 0.910 (95% CI 0.818-1.000) in the training set. In the validation set, AUC of the ROC was 0.767 (95% CI 0.459-1.000). CONCLUSIONS The responsiveness to MSC therapy appears to depend on baseline level of DDX55, AGRG6, PICAL, CTRB1, and ANXA1. Clinicians should take these factors into consideration when making decision to initiate MSC therapy in patients with severe COVID-19.
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Affiliation(s)
- Tian-Tian Li
- Senior Department of Infectious Diseases, The Fifth Medical Centre of PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing, 100039, People's Republic of China
| | - Wei-Qi Yao
- Department of Biology and Medicine, Hubei University of Technology, Wuhan, 430030, Hubei, People's Republic of China
- Wuhan Optics Valley Zhongyuan Pharmaceutical Co., Ltd., Wuhan, 430030, Hubei, People's Republic of China
| | - Hai-Bo Dong
- Wuhan Optics Valley Vcanbio Cell & Gene Technology Co., Ltd., Wuhan, 430030, Hubei, People's Republic of China
| | - Ze-Rui Wang
- Department of Gastroenterology, First Medical Center of Chinese, PLA General Hospital, Beijing, 100853, People's Republic of China
- Chinese PLA Medical School, Beijing, 100853, People's Republic of China
| | - Zi-Ying Zhang
- Senior Department of Infectious Diseases, The Fifth Medical Centre of PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing, 100039, People's Republic of China
- Chinese PLA Medical School, Beijing, 100853, People's Republic of China
| | - Meng-Qi Yuan
- Senior Department of Infectious Diseases, The Fifth Medical Centre of PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing, 100039, People's Republic of China
- Chinese PLA Medical School, Beijing, 100853, People's Republic of China
| | - Lei Shi
- Senior Department of Infectious Diseases, The Fifth Medical Centre of PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing, 100039, People's Republic of China.
- Chinese PLA Medical School, Beijing, 100853, People's Republic of China.
| | - Fu-Sheng Wang
- Senior Department of Infectious Diseases, The Fifth Medical Centre of PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing, 100039, People's Republic of China.
- Chinese PLA Medical School, Beijing, 100853, People's Republic of China.
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Anerillas LO, Wiberg M, Kingham PJ, Kelk P. Platelet lysate for expansion or osteogenic differentiation of bone marrow mesenchymal stem cells for 3D tissue constructs. Regen Ther 2023; 24:298-310. [PMID: 37588134 PMCID: PMC10425714 DOI: 10.1016/j.reth.2023.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/13/2023] [Accepted: 07/26/2023] [Indexed: 08/18/2023] Open
Abstract
Background The use of mesenchymal stem cells (MSCs) for the development of tissue-engineered constructs has advanced in recent years. However, future clinically approved products require following good manufacturing practice (GMP) guidelines. This includes using alternatives to xenogeneic-derived cell culture supplements to avoid rejection of the transplants. Consequently, human platelet lysate (PLT) has been adopted as an affordable and effective alternative to foetal bovine serum (FBS) in traditional 2D cultures. However, little is known about its effect in more advanced 3D culture systems. Methods We evaluated bone marrow MSCs (BMSCs) proliferation and CD marker expression in cells expanded in FBS or PLT-supplemented media. Differentiation capacity of the BMSCs expanded in the presence of the different supplements was evaluated in 3D type I collagen hydrogels. Furthermore, the effects of the supplements on the process of differentiation were analyzed by using qPCR and histological staining. Results Cell proliferation was greater in PLT-supplemented media versus FBS. BMSCs expanded in PLT showed similar osteogenic differentiation capacity in 3D compared with FBS expanded cells. In contrast, when cells were 3D differentiated in PLT they showed lower osteogenesis versus the traditional FBS protocol. This was also the case for adipogenic differentiation, in which FBS supplementation was superior to PLT. Conclusions PLT is a superior alternative to FBS for the expansion of MSCs without compromising their subsequent differentiation capacity in 3D. However, differentiation in PLT is impaired. Thus, PLT can be used to reduce the time required to expand the necessary cell numbers for development of 3D tissue engineered MSC constructs.
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Affiliation(s)
| | - Mikael Wiberg
- Department of Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden
- Department of Surgical & Perioperative Sciences, Section for Hand and Plastic Surgery, Umeå University, 901 87 Umeå, Sweden
| | - Paul J. Kingham
- Department of Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden
| | - Peyman Kelk
- Department of Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden
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Marinkovic M, Tran ON, Wang H, Abdul-Azees P, Dean DD, Chen XD, Yeh CK. Extracellular matrix turnover in salivary gland disorders and regenerative therapies: Obstacles and opportunities. J Oral Biol Craniofac Res 2023; 13:693-703. [PMID: 37719063 PMCID: PMC10502366 DOI: 10.1016/j.jobcr.2023.08.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/28/2023] [Indexed: 09/19/2023] Open
Abstract
Salivary gland (SG) extracellular matrix (ECM) has a major influence on tissue development, homeostasis, and tissue regeneration after injury. During aging, disease, and physical insult, normal remodeling of the SG microenvironment (i.e. ECM) becomes dysregulated, leading to alterations in matrix composition which disrupt tissue architecture/structure, alter cell activity, and negatively impact gland function. Matrix metalloproteinases (MMPs) are a large and diverse family of metalloendopeptidases which play a major role in matrix degradation and are intimately involved in regulating development and cell function; dysregulation of these enzymes leads to the production of a fibrotic matrix. In the SG this altered fibrotic ECM (or cell microenvironment) negatively impacts normal cell function and the effectiveness of gene and stem cell therapies which serve as a foundation for many SG regenerative therapies. For this reason, prospective regenerative strategies should prioritize the maintenance and/or restoration of a healthy SG ECM. Mesenchymal stem cells (MSCs) have great potential for mitigating damage to the SG microenvironment by ameliorating inflammation, reducing fibrosis, and repairing the damaged milieu of extracellular regulatory cues, including the matrix. This review addresses our current understanding of the impact of aging and disease on the SG microenvironment and suggests critical deficiencies and opportunities in ECM-targeted therapeutic interventions.
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Affiliation(s)
- Milos Marinkovic
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA
| | - Olivia N. Tran
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
| | - Hanzhou Wang
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
| | - Parveez Abdul-Azees
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA
| | - David D. Dean
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, 78249, USA
| | - Xiao-Dong Chen
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, 78249, USA
| | - Chih-Ko Yeh
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA
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Jiménez MF, Gómez-Hernández MT, Villarón EM, López-Parra M, Sánchez-Guijo F. Autologous mesenchymal stromal cells embedded with Tissucol Duo ® for prevention of air leak after anatomical lung resection: results of a prospective phase I/II clinical trial with long-term follow-up. Stem Cell Res Ther 2023; 14:313. [PMID: 37904229 PMCID: PMC10617222 DOI: 10.1186/s13287-023-03545-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 10/25/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND Prolonged air leak (PAL) is the most frequent complication after pulmonary resection. Several measures have been described to prevent the occurrence of PAL in high-risk patients, however, the potential role of mesenchymal stem cells (MSCs) applied in the parenchymal suture line to prevent postoperative air leak in this setting has not been fully addressed. OBJECTIVE To analyse the feasibility, safety and potential clinical efficacy of the implantation of autologous MSCs embedded in Tissucol Duo® as a prophylactic alternative to prevent postoperative prolonged air leak after pulmonary resection in high-risk patients. STUDY DESIGN Phase I/II single-arm prospective clinical trial. METHODS Six patients with high risk of PAL undergoing elective pulmonary resection were included. Autologous bone marrow-derived MSCs were expanded at our Good Manufacturing Practice (GMP) Facility and implanted (embedded in a Tissucol Duo® carrier) in the parenchymal suture line during pulmonary resection surgery. Patients were monitored in the early postoperative period and evaluated for possible complications or adverse reactions. In addition, all patients were followed-up to 5 years for clinical outcomes. RESULTS The median age of patients included was 66 years (range: 55-70 years), and male/female ratio was 5/1. Autologous MSCs were expanded in five cases, in one case MSCs expansion was insufficient. There were no adverse effects related to cell implantation. Regarding efficacy, median air leak duration was 0 days (range: 0-2 days). The incidence of PAL was nil. Radiologically, only one patient presented pneumothorax in the chest X-ray at discharge. No adverse effects related to the procedure were recorded during the follow-up. CONCLUSIONS The use of autologous MSCs for prevention of PAL in patients with high risk of PAL is feasible, safe and potentially effective. TRIAL REGISTRATION NO EudraCT: 2013-000535-27. CLINICALTRIALS gov idenfier: NCT02045745.
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Affiliation(s)
- Marcelo F Jiménez
- Service of Thoracic Surgery, Salamanca University Hospital, 37007, Salamanca, Spain
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain
- University of Salamanca, Salamanca, Spain
| | - María Teresa Gómez-Hernández
- Service of Thoracic Surgery, Salamanca University Hospital, 37007, Salamanca, Spain.
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain.
- University of Salamanca, Salamanca, Spain.
| | - Eva M Villarón
- Cell Therapy Area & Hematology Department, Salamanca University Hospital, Salamanca, Spain
- Network Centre for Regenerative Medicine and Cellular Therapy of Castilla y León, Salamanca, Spain
| | - Miriam López-Parra
- Cell Therapy Area & Hematology Department, Salamanca University Hospital, Salamanca, Spain
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain
- Network Centre for Regenerative Medicine and Cellular Therapy of Castilla y León, Salamanca, Spain
| | - Fermín Sánchez-Guijo
- Cell Therapy Area & Hematology Department, Salamanca University Hospital, Salamanca, Spain
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain
- University of Salamanca, Salamanca, Spain
- Network Centre for Regenerative Medicine and Cellular Therapy of Castilla y León, Salamanca, Spain
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Babaahmadi M, Tayebi B, Gholipour NM, Kamardi MT, Heidari S, Baharvand H, Eslaminejad MB, Hajizadeh-Saffar E, Hassani SN. Rheumatoid arthritis: the old issue, the new therapeutic approach. Stem Cell Res Ther 2023; 14:268. [PMID: 37741991 PMCID: PMC10518102 DOI: 10.1186/s13287-023-03473-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 08/24/2023] [Indexed: 09/25/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease of unknown etiology. The most common form of this disease is chronic inflammatory arthritis, which begins with inflammation of the synovial membrane of the affected joints and eventually leads to disability of the affected limb. Despite significant advances in RA pharmaceutical therapies and the availability of a variety of medicines on the market, none of the available medicinal therapies has been able to completely cure the disease. In addition, a significant percentage (30-40%) of patients do not respond appropriately to any of the available medicines. Recently, mesenchymal stromal cells (MSCs) have shown promising results in controlling inflammatory and autoimmune diseases, including RA. Experimental studies and clinical trials have demonstrated the high power of MSCs in modulating the immune system. In this article, we first examine the mechanism of RA disease, the role of cytokines and existing medicinal therapies. We then discuss the immunomodulatory function of MSCs from different perspectives. Our understanding of how MSCs work in suppressing the immune system will lead to better utilization of these cells as a promising tool in the treatment of autoimmune diseases.
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Affiliation(s)
- Mahnaz Babaahmadi
- Department of Applied Cell Sciences, Faculty of Basic Sciences and Advanced Medical Technologies, Royan Institute, ACECR, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat Highway, P.O. Box: 16635-148, Tehran, 1665659911, Iran
| | - Behnoosh Tayebi
- Department of Applied Cell Sciences, Faculty of Basic Sciences and Advanced Medical Technologies, Royan Institute, ACECR, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat Highway, P.O. Box: 16635-148, Tehran, 1665659911, Iran
| | - Nima Makvand Gholipour
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat Highway, P.O. Box: 16635-148, Tehran, 1665659911, Iran
| | - Mehrnaz Tayebi Kamardi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat Highway, P.O. Box: 16635-148, Tehran, 1665659911, Iran
| | - Sahel Heidari
- Department of Immunology, School of Medical Sciences, Tehran, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat Highway, P.O. Box: 16635-148, Tehran, 1665659911, Iran
- Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
| | - Mohamadreza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat Highway, P.O. Box: 16635-148, Tehran, 1665659911, Iran
| | - Ensiyeh Hajizadeh-Saffar
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat Highway, P.O. Box: 16635-148, Tehran, 1665659911, Iran.
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Seyedeh-Nafiseh Hassani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat Highway, P.O. Box: 16635-148, Tehran, 1665659911, Iran.
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat Highway, P.O. Box: 16635-148, Tehran, 1665659911, Iran.
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Neo SH, Her Z, Othman R, Tee CA, Ong LC, Wang Y, Tan I, Tan J, Yang Y, Yang Z, Chen Q, Boyer LA. Expansion of human bone marrow-derived mesenchymal stromal cells with enhanced immunomodulatory properties. Stem Cell Res Ther 2023; 14:259. [PMID: 37726837 PMCID: PMC10510228 DOI: 10.1186/s13287-023-03481-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 08/29/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) have broad potential as a cell therapy including for the treatment of drug-resistant inflammatory conditions with abnormal T cell proliferation such as graft-versus-host disease (GVHD). Clinical success, however, has been complicated by the heterogeneity of culture-expanded MSCs as well as donor variability. Here, we devise culture conditions that promote expansion of MSCs with enhanced immunomodulatory functions both in vitro and in animal models of GVHD. METHODS Human bone marrow-derived MSCs were expanded at high-confluency (MSCHC) and low-confluency state (MSCLC). Their immunomodulatory properties were evaluated with in vitro co-culture assays based on suppression of activated T cell proliferation and secretion of pro-inflammatory cytokines from activated T cells. Metabolic state of these cells was determined, while RNA sequencing was performed to explore transcriptome of these MSCs. Ex vivo expanded MSCHC or MSCLC was injected into human peripheral blood mononuclear cells (PBMC)-induced GVHD mouse model to determine their in vivo therapeutic efficacy based on clinical grade scoring, human CD45+ blood count and histopathological examination. RESULTS As compared to MSCLC, MSCHC significantly reduced both the proliferation of anti-CD3/CD28-activated T cells and secretion of pro-inflammatory cytokines upon MSCHC co-culture across several donors even in the absence of cytokine priming. Mechanistically, metabolic analysis of MSCHC prior to co-culture with activated T cells showed increased glycolytic metabolism and lactate secretion compared to MSCLC, consistent with their ability to inhibit T cell proliferation. Transcriptome analysis further revealed differential expression of immunomodulatory genes including TRIM29, BPIFB4, MMP3 and SPP1 in MSCHC as well as enriched pathways including cytokine-cytokine receptor interactions, cell adhesion and PI3K-AKT signalling. Lastly, we demonstrate in a human PBMC-induced GVHD mouse model that delivery of MSCHC showed greater suppression of inflammation and improved outcomes compared to MSCLC and saline controls. CONCLUSION Our study provides evidence that ex vivo expansion of MSCs at high confluency alters the metabolic and transcriptomic states of these cells. Importantly, this approach maximizes the production of MSCs with enhanced immunomodulatory functions without priming, thus providing a non-invasive and generalizable strategy for improving the use of MSCs for the treatment of inflammatory diseases.
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Affiliation(s)
- Shu Hui Neo
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
| | - Zhisheng Her
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
- Invivocue Pte Ltd, 51 Science Park Road, #01-11/13 The Aries, Singapore Science Park II, Singapore, 117586, Republic of Singapore
| | - Rashidah Othman
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
| | - Ching Ann Tee
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
| | - Li Ching Ong
- Invivocue Pte Ltd, 51 Science Park Road, #01-11/13 The Aries, Singapore Science Park II, Singapore, 117586, Republic of Singapore
| | - Yuehua Wang
- Invivocue Pte Ltd, 51 Science Park Road, #01-11/13 The Aries, Singapore Science Park II, Singapore, 117586, Republic of Singapore
| | - Irwin Tan
- Invivocue Pte Ltd, 51 Science Park Road, #01-11/13 The Aries, Singapore Science Park II, Singapore, 117586, Republic of Singapore
| | - Jaylen Tan
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
| | - Yanmeng Yang
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
| | - Zheng Yang
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
- Department of Orthopaedic Surgery, National University of Singapore, NUHS, 1E Kent Ridge RoadTower Block 11, Singapore, 119288, Republic of Singapore
- NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, 27 Medical Drive, DSO (Kent Ridge) Building, Level 4, Singapore, 117510, Republic of Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore.
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore, 117545, Republic of Singapore.
| | - Laurie A Boyer
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore.
- Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
- Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
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Ortiz GGR, Zaidi NH, Saini RS, Ramirez Coronel AA, Alsandook T, Hadi Lafta M, Arias-Gonzáles JL, Amin AH, Maaliw Iii RR. The developing role of extracellular vesicles in autoimmune diseases: special attention to mesenchymal stem cell-derived extracellular vesicles. Int Immunopharmacol 2023; 122:110531. [PMID: 37437434 DOI: 10.1016/j.intimp.2023.110531] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/10/2023] [Accepted: 06/16/2023] [Indexed: 07/14/2023]
Abstract
Autoimmune diseases are complex, chronic inflammatory conditions initiated by the loss of immunological tolerance to self-antigens. Nowadays, there is no effective and useful therapy for autoimmune diseases, and the existing medications have some limitations due to their nonspecific targets and side effects. During the last few decades, it has been established that mesenchymal stem cells (MSCs) have immunomodulatory functions. It is proposed that MSCs can exert an important therapeutic effect on autoimmune disorders. In parallel with these findings, several investigations have shown that MSCs alleviate autoimmune diseases. Intriguingly, the results of studies have demonstrated that the effective roles of MSCs in autoimmune diseases do not depend on direct intercellular communication but on their ability to release a wide spectrum of paracrine mediators such as growth factors, cytokines and extracellular vehicles (EVs). EVs that range from 50 to 5,000 nm were produced by almost any cell type, and these nanoparticles participate in homeostasis and intercellular communication via the transfer of a broad range of biomolecules such as modulatory proteins, nucleic acids (DNA and RNA), lipids, cytokines, and metabolites. EVs derived from MSCs display the exact properties of MSCs and can be safer and more beneficial than their parent cells. In this review, we will discuss the features of MSCs and their EVs, EVs biogenesis, and their cargos, and then we will highlight the existing discoveries on the impacts of EVs from MSCs on autoimmune diseases such as multiple sclerosis, arthritis rheumatic, inflammatory bowel disease, Type 1 diabetes mellitus, systemic lupus erythematosus, autoimmune liver diseases, Sjögren syndrome, and osteoarthritis, suggesting a potential alternative for autoimmune conditions therapy.
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Affiliation(s)
- Geovanny Genaro Reivan Ortiz
- Laboratory of Basic Psychology, Behavioral Analysis and Programmatic Development (PAD-LAB), Catholic University of Cuenca, Cuenca, Ecuador
| | - Neelam Hazoor Zaidi
- Umanand Prasad School of Medicine and Health Science, The University of Fiji, Saweni Campus, Lautoka, Fiji
| | | | | | - Tahani Alsandook
- Dentistry Department, Al-Turath University College, Baghdad, Iraq
| | | | | | - Ali H Amin
- Zoology Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - Renato R Maaliw Iii
- College of Engineering, Southern Luzon State University, Lucban, Quezon, Philippines.
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Madrigal M, Fernández PL, Lleonart R, Carreño L, Villalobos Gorday KA, Rodríguez E, de Cupeiro K, Restrepo CM, Rao KSJ, Riordan NH. Comparison of Cost and Potency of Human Mesenchymal Stromal Cell Conditioned Medium Derived from 2- and 3-Dimensional Cultures. Bioengineering (Basel) 2023; 10:930. [PMID: 37627815 PMCID: PMC10451979 DOI: 10.3390/bioengineering10080930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/31/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023] Open
Abstract
Mesenchymal stromal cell (MSC)-derived products, such as trophic factors (MTFs), have anti-inflammatory properties that make them attractive for cell-free treatment. Three-dimensional (3D) culture can enhance these properties, and large-scale expansion using a bioreactor can reduce manufacturing costs. Three lots of MTFs were obtained from umbilical cord MSCs produced by either monolayer culture (Monol MTF) or using a 3D microcarrier in a spinner flask dynamic system (Bioreactor MTF). The resulting MTFs were tested and compared using anti-inflammatory potency assays in two different systems: (1) a phytohemagglutinin-activated peripheral blood mononuclear cell (PBMNC) system and (2) a lipopolysaccharide (LPS)-activated macrophage system. Cytokine expression by macrophages was measured via RT-PCR. The production costs of hypothetical units of anti-inflammatory effects were calculated using the percentage of TNF-α inhibition by MTF exposure. Bioreactor MTFs had a higher inhibitory effect on TNF (p < 0.01) than monolayer MTFs (p < 0.05). The anti-inflammatory effect of Bioreactor MTFs on IL-1β, TNF-α, IL-8, IL-6, and MIP-1 was significantly higher than that of monolayer MTFs. The production cost of 1% inhibition of TNF-α was 11-40% higher using monolayer culture compared to bioreactor-derived MTFs. A 3D dynamic culture was, therefore, able to produce high-quality MTFs, with robust anti-inflammatory properties, more efficiently than monolayer static systems.
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Affiliation(s)
- Marialaura Madrigal
- MediStem Panama Inc., Panama City 7144, Panama
- Department of Biotechnology, Acharya Nagarjuna University, Guntur 522510, India
- Centro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP), Panama City 7144, Panama
| | - Patricia L. Fernández
- Centro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP), Panama City 7144, Panama
| | - Ricardo Lleonart
- Centro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP), Panama City 7144, Panama
| | | | | | | | | | - Carlos M. Restrepo
- Centro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP), Panama City 7144, Panama
| | - K. S. Jagannatha Rao
- Department of Biotechnology, Konenru Lakshmaiah Education Foundation (KLEF) deemed to be University, Vaddeswaram 522302, India
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35
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Yang G, Fan X, Liu Y, Jie P, Mazhar M, Liu Y, Dechsupa N, Wang L. Immunomodulatory Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells. Stem Cell Rev Rep 2023; 19:1214-1231. [PMID: 37058201 PMCID: PMC10103048 DOI: 10.1007/s12015-023-10539-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 04/15/2023]
Abstract
Mesenchymal stem cells (MSCs) are regarded as highly promising cells for allogeneic cell therapy, owing to their multipotent nature and ability to display potent and varied functions in different diseases. The functions of MSCs, including native immunomodulation, high self-renewal characteristic, and secretory and trophic properties, can be employed to improve the immune-modulatory functions in diseases. MSCs impact most immune cells by directly contacting and/or secreting positive microenvironmental factors to influence them. Previous studies have reported that the immunomodulatory role of MSCs is basically dependent on their secretion ability from MSCs. This review discusses the immunomodulatory capabilities of MSCs and the promising strategies to successfully improve the potential utilization of MSCs in clinical research.
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Affiliation(s)
- Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Acupuncture and Rehabilitation Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xuehui Fan
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany
| | - Yingchun Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Pingping Jie
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Yong Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China.
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Xue Y, Mei H, Chen Y, Griffin JD, Liu Q, Weisberg E, Yang J. Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS-CoV-2. MedComm (Beijing) 2023; 4:e254. [PMID: 37193304 PMCID: PMC10183156 DOI: 10.1002/mco2.254] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 02/11/2023] [Accepted: 03/07/2023] [Indexed: 05/18/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has affected a large portion of the global population, both physically and mentally. Current evidence suggests that the rapidly evolving coronavirus subvariants risk rendering vaccines and antibodies ineffective due to their potential to evade existing immunity, with enhanced transmission activity and higher reinfection rates that could lead to new outbreaks across the globe. The goal of viral management is to disrupt the viral life cycle as well as to relieve severe symptoms such as lung damage, cytokine storm, and organ failure. In the fight against viruses, the combination of viral genome sequencing, elucidation of the structure of viral proteins, and identifying proteins that are highly conserved across multiple coronaviruses has revealed many potential molecular targets. In addition, the time- and cost-effective repurposing of preexisting antiviral drugs or approved/clinical drugs for these targets offers considerable clinical advantages for COVID-19 patients. This review provides a comprehensive overview of various identified pathogenic targets and pathways as well as corresponding repurposed approved/clinical drugs and their potential against COVID-19. These findings provide new insight into the discovery of novel therapeutic strategies that could be applied to the control of disease symptoms emanating from evolving SARS-CoV-2 variants.
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Affiliation(s)
- Yiying Xue
- Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Husheng Mei
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical ScienceChinese Academy of SciencesHefeiChina
- University of Science and Technology of ChinaHefeiAnhuiChina
| | - Yisa Chen
- Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - James D. Griffin
- Department of Medical Oncology, Dana‐Farber Cancer InstituteBostonMassachusettsUSA
- Department of Medicine, Harvard Medical SchoolBostonMassachusettsUSA
| | - Qingsong Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical ScienceChinese Academy of SciencesHefeiChina
- University of Science and Technology of ChinaHefeiAnhuiChina
- Hefei Cancer HospitalChinese Academy of SciencesHefeiChina
| | - Ellen Weisberg
- Department of Medical Oncology, Dana‐Farber Cancer InstituteBostonMassachusettsUSA
- Department of Medicine, Harvard Medical SchoolBostonMassachusettsUSA
| | - Jing Yang
- Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and TechnologyTongji UniversityShanghaiChina
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical ScienceChinese Academy of SciencesHefeiChina
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Meng S, Tang C, Deng M, Yuan J, Fan Y, Gao S, Feng Y, Yang J, Chen C. Tropoelastin-Pretreated Exosomes from Adipose-Derived Stem Cells Improve the Synthesis of Cartilage Matrix and Alleviate Osteoarthritis. J Funct Biomater 2023; 14:jfb14040203. [PMID: 37103293 PMCID: PMC10143921 DOI: 10.3390/jfb14040203] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/24/2023] [Accepted: 04/03/2023] [Indexed: 04/28/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have recently been widely used to treat osteoarthritis (OA). Our prior research shows that tropoelastin (TE) increases MSC activity and protects knee cartilage from OA-related degradation. The underlying mechanism might be that TE regulates the paracrine of MSCs. Exosomes (Exos), the paracrine secretion of MSCs, have been found to protect chondrocytes, reduce inflammation, and preserve the cartilage matrix. In this study, we used Exos derived from TE-pretreated adipose-derived stem cells (ADSCs) (TE-ExoADSCs) as an injection medium, and compared it with Exos derived from unpretreated ADSCs (ExoADSCs). We found that TE-ExoADSCs could effectively enhance the matrix synthesis of chondrocytes in vitro. Moreover, TE pretreatment increased the ability of ADSCs to secrete Exos. In addition, compared with ExoADSCs, TE-ExoADSCs exhibited therapeutic effects in the anterior cruciate ligament transection (ACLT)-induced OA model. Further, we observed that TE altered the microRNA expression in ExoADSCs and identified one differentially upregulated microRNA: miR-451-5p. In conclusion, TE-ExoADSCs helped maintain the chondrocyte phenotype in vitro, and promoted cartilage repair in vivo. These therapeutic effects might be related with the altered expression of miR-451-5p in the ExoADSCs. Thus, the intra-articular delivery of Exos derived from ADSCs with TE pretreatment could be a new approach to treat OA.
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Affiliation(s)
- Shuo Meng
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Cong Tang
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Muhai Deng
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Jie Yuan
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Yanli Fan
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Shasha Gao
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Yong Feng
- Department of Orthopaedic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing 400014, China
| | - Junjun Yang
- Key Laboratory of Biorheological Science and Technology, College of Bioengineering, Chongqing University, Ministry of Education, Chongqing 400044, China
| | - Cheng Chen
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
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Liao CD, Chen HC, Huang MH, Liou TH, Lin CL, Huang SW. Comparative Efficacy of Intra-Articular Injection, Physical Therapy, and Combined Treatments on Pain, Function, and Sarcopenia Indices in Knee Osteoarthritis: A Network Meta-Analysis of Randomized Controlled Trials. Int J Mol Sci 2023; 24:6078. [PMID: 37047058 PMCID: PMC10094194 DOI: 10.3390/ijms24076078] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/16/2023] [Accepted: 03/20/2023] [Indexed: 04/14/2023] Open
Abstract
Knee osteoarthritis (KOA) is associated with a high risk of sarcopenia. Both intra-articular injections (IAIs) and physical therapy (PT) exert benefits in KOA. This network meta-analysis (NMA) study aimed to identify comparative efficacy among the combined treatments (IAI+PT) in patients with KOA. Seven electronic databases were systematically searched from inception until January 2023 for randomized controlled trials (RCTs) reporting the effects of IAI+PT vs. IAI or PT alone in patients with KOA. All RCTs which had treatment arms of IAI agents (autologous conditioned serum, botulinum neurotoxin type A, corticosteroids, dextrose prolotherapy (DxTP), hyaluronic acid, mesenchymal stem cells (MSC), ozone, platelet-rich plasma, plasma rich in growth factor, and stromal vascular fraction of adipose tissue) in combination with PT (exercise therapy, physical agent modalities (electrotherapy, shockwave therapy, thermal therapy), and physical activity training) were included in this NMA. A control arm receiving placebo IAI or usual care, without any other IAI or PT, was used as the reference group. The selected RCTs were analyzed through a frequentist method of NMA. The main outcomes included pain, global function (GF), and walking capability (WC). Meta-regression analyses were performed to explore potential moderators of the treatment efficacy. We included 80 RCTs (6934 patients) for analyses. Among the ten identified IAI+PT regimens, DxTP plus PT was the most optimal treatment for pain reduction (standard mean difference (SMD) = -2.54) and global function restoration (SMD = 2.28), whereas MSC plus PT was the most effective for enhancing WC recovery (SMD = 2.54). More severe KOA was associated with greater changes in pain (β = -2.52) and WC (β = 2.16) scores. Combined IAI+PT treatments afford more benefits than do their corresponding monotherapies in patients with KOA; however, treatment efficacy is moderated by disease severity.
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Affiliation(s)
- Chun-De Liao
- International Ph.D. Program in Gerontology and Long-Term Care, College of Nursing, Taipei Medical University, Taipei 110301, Taiwan
- Department of Physical Medicine and Rehabilitation, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan
| | - Hung-Chou Chen
- Department of Physical Medicine and Rehabilitation, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan
- Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
| | - Mao-Hua Huang
- Department of Biochemistry, University of Washington, Seattle, WA 98015, USA
| | - Tsan-Hon Liou
- Department of Physical Medicine and Rehabilitation, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan
- Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
| | - Che-Li Lin
- Department of Orthopedic Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Shih-Wei Huang
- Department of Physical Medicine and Rehabilitation, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan
- Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
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Fang Y, Qiu W, Li X, Jin Q, Yan H, Yu N, Zhao J, Tan Y, Zhao Z. A combination of umbilical cord mesenchymal stem cells and monosialotetrahexosy 1 ganglioside alleviates neuroinflammation in traumatic brain injury. Exp Brain Res 2023; 241:713-726. [PMID: 36694046 DOI: 10.1007/s00221-023-06554-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/11/2023] [Indexed: 01/26/2023]
Abstract
Neuro-inflammation and activated microglia play important roles in neuron damage in the traumatic brain injury (TBI). In this study, we determined the effect of neural network reconstruction after human umbilical cord mesenchymal stem cells (UMSCs) combined with monosialotetrahexosy 1 ganglioside (GM1) transplantation and the effect on the neuro-inflammation and polarization of microglia in a rat model of TBI, which was established in male rats using a fluid percussion brain injury device. Rats survived until day 7 after TBI were randomly treated with normal control (NC), saline (NS), GM1, UMSCs, and GM1 plus UMSCs. Modified neurological severity score (mNSS) was assessed on days 7 and 14, and the brain tissue of the injured region was collected. Immunofluorescence, RT-PCR, and western blot analysis found that inhibitory neuro-inflammatory cytokines TGF-β and CD163 protein expression levels in injured brain tissues were significantly increased in rats treated with GM1 + UMSCs, GM1, or UMSCs and were up-regulated compared to saline-treated rats. Neuro-inflammatory cytokines IL-6, COX-2 and iNOS protein expressions were down-regulated compared to rats treated with saline. The protein expression levels of NE, NF-200, MAP-2 and β-tubulin III were increased in the injured brain tissues from rats treated with GM1 + UMSCs, or GM1 and UMSCs alone compared to those in the rats treated with NS. The protein expression levels in rats treated with GM1 plus UMSCs were most significant on day 7 following UMSC transplantation. The rats treated with GM1 plus UMSCs had the lowest mNSS compared with that in the other groups. These data suggest that UMSCs and GM1 promote neural network reconstruction and reduce the neuro-inflammation and neurodegeneration through coordinating injury local immune inflammatory microenvironment to promote the recovery of neurological functions in the TBI.
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Affiliation(s)
- Yanwei Fang
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Wenna Qiu
- Department of Neonatology, Hebei Children's Hospital, Shijiazhuang, Hebei, China
| | - Xin Li
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Qianxu Jin
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Hongshan Yan
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Ning Yu
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Jianhui Zhao
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Yi Tan
- Shandong Qilu Cell Therapy Engineering Technology Co., Ltd. Jinan, Shandong, China
| | - Zongmao Zhao
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, Hebei, People's Republic of China.
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40
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Ma Y, Zhao X, Chen J, Chen X, Fan W, Sun Y, Lin Z, Fu L, Zou H, Mou X. Umbilical cord mesenchymal‐stem‐cell‐derived nanovesicles as a novel strategy to promote wound healing in diabetes. NANO SELECT 2023. [DOI: 10.1002/nano.202200211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023] Open
Affiliation(s)
- Ying‐Yu Ma
- Center for Plastic & Reconstructive Surgery Department of Plastic and Reconstructive Surgery Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
| | - Xin Zhao
- Center for Plastic & Reconstructive Surgery Department of Plastic and Reconstructive Surgery Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
- Key Laboratory of Cancer Molecular Diagnosis and Individualized Therapy of Zhejiang Province Clinical Research Institute Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
- College of Pharmacy Hangzhou Medical College Hangzhou China
| | - Jin‐Yang Chen
- Zhejiang Health future Biomedicine Co., Ltd Hangzhou China
| | - Xiao‐Yi Chen
- Center for Plastic & Reconstructive Surgery Department of Plastic and Reconstructive Surgery Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
- Key Laboratory of Cancer Molecular Diagnosis and Individualized Therapy of Zhejiang Province Clinical Research Institute Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
| | - Wei‐Jiao Fan
- Key Laboratory of Cancer Molecular Diagnosis and Individualized Therapy of Zhejiang Province Clinical Research Institute Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
| | - Yi Sun
- Center for Plastic & Reconstructive Surgery Department of Plastic and Reconstructive Surgery Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
| | - Zhi‐Wei Lin
- Zhejiang Health future Biomedicine Co., Ltd Hangzhou China
| | - Luo‐Qin Fu
- Center for Plastic & Reconstructive Surgery Department of Plastic and Reconstructive Surgery Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
- Key Laboratory of Cancer Molecular Diagnosis and Individualized Therapy of Zhejiang Province Clinical Research Institute Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
| | - Hai Zou
- Department of Oncology Shanghai Medical College Fudan University Shanghai China
- Department of Critical Care Fudan University Shanghai Cancer Center Shanghai China
| | - Xiao‐Zhou Mou
- Center for Plastic & Reconstructive Surgery Department of Plastic and Reconstructive Surgery Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
- Key Laboratory of Cancer Molecular Diagnosis and Individualized Therapy of Zhejiang Province Clinical Research Institute Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou China
- College of Pharmacy Hangzhou Medical College Hangzhou China
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41
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Korchak JA, Wiest EF, Zubair AC. How do we assess batch-to-batch consistency between extracellular vesicle products? Transfusion 2023; 63:279-287. [PMID: 36329638 DOI: 10.1111/trf.17156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 09/01/2022] [Accepted: 09/29/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Extracellular vesicles (EVs) have gained interest in the field of regenerative and transfusion medicine. Specifically, current Good Manufacturing Practice (cGMP)-grade EVs produced by mesenchymal stromal cells (MSCs) are an intriguing option for cell-free therapeutics. With the development of cGMP-grade EV products, a simple and reliable method for batch-to-batch consistency is needed. STUDY DESIGN AND METHODS The objective of this study was to validate a method to semiquantitatively assess the batch-to-batch consistency of isolated EVs. A multiplex bead-based flow cytometric assay containing 37 surface markers and 2 assay control antibody-coated capture beads was validated. Detection limits (n = 10 buffer samples), repeatability (n = 9 EV samples), and intra-observer reproducibility over 2 days (n = 10 EV batches) were assessed. A Spearman correlation matrix was used to evaluate the batch-to-batch consistency of independently isolated EV products (n = 37 surface markers). Batches with a Spearman correlation coefficient ≥0.9 and p < 0.05 were considered statistically indistinguishable from previous batches. RESULTS This assay demonstrated robust repeatability as well as intra- and inter-assay reproducibility. In-house batches of EVs were significantly correlated (r ≥ 0.90; p ≤ 1×10-14 ). Compared with buffer, EV batches had correlation coefficients near zero (r ≤ -0.10; p ≥ 0.12). Commercially sourced EVs significantly correlated with in-house EV batches, but fell below the 90% correlation cutoff (r ≤ 0.71; p ≤ 0.0004). DISCUSSION This time-efficient and technically simple assay offers a robust method of quality control for assessing the batch-to-batch reproducibility of cGMP-grade EV products.
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Affiliation(s)
- Jennifer A Korchak
- Center for Regenerative Biotherapeutics, Jacksonville, Florida, USA.,Department of Laboratory Medicine and Pathology, Jacksonville, Florida, USA
| | - Elani F Wiest
- Center for Regenerative Biotherapeutics, Jacksonville, Florida, USA
| | - Abba C Zubair
- Center for Regenerative Biotherapeutics, Jacksonville, Florida, USA.,Department of Laboratory Medicine and Pathology, Jacksonville, Florida, USA.,Sheikh Shakhbout Medical City-Mayo Clinic Joint Venture, Abu Dhabi, UAE
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42
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Weber L, Lee BS, Imboden S, Hsieh CJ, Lin NY. Phenotyping senescent mesenchymal stromal cells using AI image translation. CURRENT RESEARCH IN BIOTECHNOLOGY 2023; 5:100120. [PMID: 38045568 PMCID: PMC10691861 DOI: 10.1016/j.crbiot.2023.100120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) offer promising potential in biomedical research, clinical therapeutics, and immunomodulatory therapies due to their ease of isolation and multipotent, immunoprivileged, and immunosuppersive properties. Extensive efforts have focused on optimizing the cell isolation and culture methods to generate scalable, therapeutically-relevant MSCs for clinical applications. However, MSC-based therapies are often hindered by cell heterogeneity and inconsistency of therapeutic function caused, in part, by MSC senescence. As such, noninvasive and molecular-based MSC characterizations play an essential role in assuring the consistency of MSC functions. Here, we demonstrated that AI image translation algorithms can effectively predict immunofluorescence images of MSC senescence markers from phase contrast images. We showed that the expression level of senescence markers including senescence-associated beta-galactosidase (SABG), p16, p21, and p38 are accurately predicted by deep-learning models for Doxorubicin-induced MSC senescence, irradiation-induced MSC senescence, and replicative MSC senescence. Our AI model distinguished the non-senescent and senescent MSC populations and simultaneously captured the cell-to-cell variability within a population. Our microscopy-based phenotyping platform can be integrated with cell culture routines making it an easily accessible tool for MSC engineering and manufacturing.
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Affiliation(s)
- Leya Weber
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles 90095, CA, United States
| | - Brandon S. Lee
- Department of Bioengineering, University of California, Los Angeles 90095, CA, United States
| | - Sara Imboden
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles 90095, CA, United States
| | - Cho-Jui Hsieh
- Department of Computer Science, University of California, Los Angeles 90095, CA, United States
| | - Neil Y.C. Lin
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles 90095, CA, United States
- Department of Bioengineering, University of California, Los Angeles 90095, CA, United States
- California NanoSystems Institute, University of California, Los Angeles 90095, CA, United States
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles 90095, CA, United States
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles 90095, CA, United States
- Broad Stem Cell Center, University of California, Los Angeles 90095, CA, United States
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Liang Z, Zhang G, Gan G, Naren D, Liu X, Liu H, Mo J, Lu S, Nie D, Ma L. Preclinical Short-term and Long-term Safety of Human Bone Marrow Mesenchymal Stem Cells. Cell Transplant 2023; 32:9636897231213271. [PMID: 38059278 PMCID: PMC10704945 DOI: 10.1177/09636897231213271] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 10/20/2023] [Accepted: 10/25/2023] [Indexed: 12/08/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have become a promising therapeutic method. More safety data are needed to support clinical studies in more diseases. The aim of this study was to investigate the short- and long-term safety of human bone marrow-derived MSCs (hBMMSCs) in mice. In the present study, we injected control (saline infusion only), low (1.0 × 106/kg), medium (1.0 × 107/kg), and high (1.0 × 108/kg) concentrations of hBMMSCs into BALB/c mice. The safety of the treatment was evaluated by observing changes in the general condition, hematology, biochemical indices, pathology of vital organs, lymphocyte subsets, and immune factor levels on days 14 and 150. In the short-term toxicity test, no significant abnormalities were observed in the hematological and biochemical parameters between the groups injected with hBMMSCs, and no significant damage was observed in the major organs, such as the liver and lung. In addition, no significant differences were observed in the toxicity-related parameters among the groups in the long-term toxicity test. Our study also demonstrates that mice infused with different doses of hBMMSCs do not show abnormal immune responses in either short-term or long-term experiments. We confirmed that hBMMSCs are safe through a 150-day study, demonstrating that this is a safe and promising therapy and offering preliminary safety evidence to promote future clinical applications of hBMMSCs in different diseases.
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Affiliation(s)
- Ziyang Liang
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Guoyang Zhang
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - GuangTing Gan
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Duolan Naren
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Hematology, Guangdong Provincial Hospital of Traditional Chinese Medicine, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoyan Liu
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hongyun Liu
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jiani Mo
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shengqin Lu
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Danian Nie
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Liping Ma
- Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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Oz Oyar E, Aciksari A, Azak Pazarlar B, Egilmez CB, Duruksu G, Rencber SF, Yardimoglu Yilmaz M, Ozturk A, Yazir Y. The therapeutical effects of damage-specific stress induced exosomes on the cisplatin nephrotoxicity IN VIVO. Mol Cell Probes 2022; 66:101861. [PMID: 36162595 DOI: 10.1016/j.mcp.2022.101861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 09/09/2022] [Accepted: 09/09/2022] [Indexed: 12/30/2022]
Abstract
Cisplatin is one of the metal containing drugs for the solid cancer treatments. However, its side-effects limit its application in the cancer treatment. Stem cell therapy is a promising treatment for the tissue damage caused by the chemotherapeutic agents, like cisplatin. Exosomes secreted by mesenchymal stem cells (MSCs) could be used for cell-free regenerative treatment, but their potency and reproducibility are questionable. In this study, the microenvironment of the renal tubular epithelial cells was mimicked by coculture of endothelial-, renal proximal tubule epithelial- and fibroblast cells. Cisplatin was applied to this tricell culture model, and the secreted rescue signals were collected and used to induce MSCs. From these stress-induced MSCs, the (stress-induced) exosomes were collected and used for the cell-free therapeutic treatment of cisplatin-treated rats with acute kidney injury. The composition of the stress-induces exosomes was compared with the non-induced exosomes and found that the expression of some critical factors for cell proliferation, repair mechanism and oxidative stress was improved. The cisplatin-damaged renal tissue showed substantial recovery after the treatment with stress-induced exosomes compared to the treatment with non-induced exosomes. Although, the non-induced exosomes showed their activity mostly as cytoprotective, the induced exosomes further involved actively in the tissue regeneration, like MSCs. It was shown that the exosomes could be reprogrammed to improve their therapeutic effect to be used in cell-free regenerative medicine. Further, cisplatin-induced tissue damage in the kidney might be effectively prevented and used for tissue regeneration by use of induced exosomes generated for a particular damage.
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Affiliation(s)
- Eser Oz Oyar
- Department of Physiology, Faculty of Medicine, Izmir Katip Celebi University, Izmir, Turkey.
| | - Aysegul Aciksari
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Izmit, Kocaeli, Turkey.
| | - Burcu Azak Pazarlar
- Department of Physiology, Faculty of Medicine, Izmir Katip Celebi University, Izmir, Turkey.
| | - Cansu Bilister Egilmez
- Department of Physiology, Faculty of Medicine, Izmir Katip Celebi University, Izmir, Turkey.
| | - Gokhan Duruksu
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Izmit, Kocaeli, Turkey; Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University, Izmit, Kocaeli, Turkey.
| | - Selenay Furat Rencber
- Department of Histology and Embryology, Faculty of Medicine, Kocaeli University, Izmit, Kocaeli, Turkey.
| | - Melda Yardimoglu Yilmaz
- Department of Histology and Embryology, Faculty of Medicine, Kocaeli University, Izmit, Kocaeli, Turkey.
| | - Ahmet Ozturk
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Izmit, Kocaeli, Turkey.
| | - Yusufhan Yazir
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Izmit, Kocaeli, Turkey; Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University, Izmit, Kocaeli, Turkey; Department of Histology and Embryology, Faculty of Medicine, Kocaeli University, Izmit, Kocaeli, Turkey.
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Shephard MT, Merkhan MM, Forsyth NR. Human Mesenchymal Stem Cell Secretome Driven T Cell Immunomodulation Is IL-10 Dependent. Int J Mol Sci 2022; 23:13596. [PMID: 36362383 PMCID: PMC9658100 DOI: 10.3390/ijms232113596] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 09/01/2023] Open
Abstract
The Human Mesenchymal Stem Cell (hMSC) secretome has pleiotropic effects underpinning its therapeutic potential. hMSC serum-free conditioned media (SFCM) contains a variety of cytokines, with previous studies linking a changed secretome composition to physoxia. The Jurkat T cell model allowed the efficacy of SFCM vs. serum-free media (SFM) in the suppression of immunological aspects, including proliferation and polarisation, to be explored. Cell growth in SFM was higher [(21% O2 = 5.3 × 105 ± 1.8 × 104 cells/mL) and (2% O2 = 5.1 × 105 ± 3.0 × 104 cells/mL)], compared to SFCM [(21% O2 = 2.4 × 105 ± 2.5 × 104 cells/mL) and (2% O2 = 2.2 × 105 ± 5.8 × 103 cells/mL)]. SFM supported IL-2 release following activation [(21% O2 = 5305 ± 211 pg/mL) and (2% O2 = 5347 ± 327 pg/mL)] whereas SFCM suppressed IL-2 secretion [(21% O2 = 2461 ± 178 pg/mL) and (2% O2 = 1625 ± 159 pg/mL)]. Anti-inflammatory cytokines, namely IL-4, IL-10, and IL-13, which we previously confirmed as components of hMSC SFCM, were tested. IL-10 neutralisation in SFCM restored proliferation in both oxygen environments (SFM/SFCM+antiIL-10 ~1-fold increase). Conversely, IL-4/IL-13 neutralisation showed no proliferation restoration [(SFM/SFM+antiIL-4 ~2-fold decrease), and (SFM/SFCM+antiIL-13 ~2-fold decrease)]. Present findings indicate IL-10 played an immunosuppressive role by reducing IL-2 secretion. Identification of immunosuppressive components of the hMSC secretome and a mechanistic understanding of their action allow for the advancement and refinement of potential future cell-free therapies.
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Affiliation(s)
- Matthew T. Shephard
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Staffordshire ST4 7QB, UK
| | - Marwan M. Merkhan
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Staffordshire ST4 7QB, UK
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul 41002, Iraq
| | - Nicholas R. Forsyth
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Staffordshire ST4 7QB, UK
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Huang Y, Zhu M, Liu Z, Hu R, Li F, Song Y, Geng Y, Ma W, Song K, Zhang M. Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects. Front Immunol 2022; 13:997808. [PMID: 36389844 PMCID: PMC9646528 DOI: 10.3389/fimmu.2022.997808] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/17/2022] [Indexed: 12/31/2022] Open
Abstract
Premature ovarian failure (POF) is a common female reproductive disorder and characterized by menopause, increased gonadotropin levels and estrogen deficiency before the age of 40 years old. The etiologies and pathogenesis of POF are not fully clear. At present, hormone replacement therapy (HRT) is the main treatment options for POF. It helps to ameliorate perimenopausal symptoms and related health risks, but can't restore ovarian function and fertility fundamentally. With the development of regenerative medicine, bone marrow mesenchymal stem cells (BMSCs) have shown great potential for the recovery of ovarian function and fertility based on the advantages of abundant sources, high capacity for self-renewal and differentiation, low immunogenicity and less ethical considerations. This systematic review aims to summarize the possible therapeutic mechanisms of BMSCs for POF. A detailed search strategy of preclinical studies and clinical trials on BMSCs and POF was performed on PubMed, MEDLINE, Web of Science and Embase database. A total of 21 studies were included in this review. Although the standardization of BMSCs need more explorations, there is no doubt that BMSCs transplantation may represent a prospective therapy for POF. It is hope to provide a theoretical basis for further research and treatment for POF.
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Affiliation(s)
- Yanjing Huang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengdi Zhu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhuo Liu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Runan Hu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fan Li
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yufan Song
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuli Geng
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenwen Ma
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kunkun Song
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Mingmin Zhang, ; Kunkun Song,
| | - Mingmin Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Mingmin Zhang, ; Kunkun Song,
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Differentiation Capacity of Bone Marrow-Derived Rat Mesenchymal Stem Cells from DsRed and Cre Transgenic Cre/ loxP Models. Cells 2022; 11:cells11172769. [PMID: 36078177 PMCID: PMC9455627 DOI: 10.3390/cells11172769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/23/2022] [Accepted: 08/26/2022] [Indexed: 11/26/2022] Open
Abstract
Cre/loxP recombination is a well-established technique increasingly used for modifying DNA both in vitro and in vivo. Nucleotide alterations can be edited in the genomes of mammalian cells, and genetic switches can be designed to target the expression or excision of a gene in any tissue at any time in animal models. In this study, we propose a system which worked via the Cre/loxP switch gene and DsRed/emGFP dual-color fluorescence imaging. Mesenchymal stem cells (MSCs) can be used to regenerate damaged tissue because of their differentiation capacity. Although previous studies have presented evidence of fusion of transplanted MSCs with recipient cells, the possibility of fusion in such cases remains debated. Moreover, the effects and biological implications of the fusion of MSCs at the tissue and organ level have not yet been elucidated. Thus, the method for determining this issue is significant and the models we proposed can illustrate the question. However, the transgenic rats exhibited growth slower than that of wild-type rats over several weeks. The effects on the stemness, proliferation, cell cycle, and differentiation ability of bone marrow–derived rat MSCs (BM-rMSCs) from the models were examined to ensure our design was appropriate for the in vivo application. We demonstrated that MSC surface markers were maintained in DsRed and Cre transgenic rMSCs (DsRed-rMSCs and Cre-rMSCs, respectively). A WST-8 assay revealed decreased proliferative activity in these DsRed-rMSCs and Cre-rMSCs; this result was validated through cell counting. Furthermore, cell cycle analysis indicated a decrease in the proportion of G1-phase cells and a concomitant increase in the proportion of S-phase cells. The levels of cell cycle–related proteins also decreased in the DsRed-rMSCs and Cre-rMSCs, implying decelerated phase transition. However, the BM-rMSCs collected from the transgenic rats did not exhibit altered adipogenesis, osteogenesis, or chondrogenesis. The specific markers of these types of differentiation were upregulated after induction. Therefore, BM-rMSCs from DsRed and Cre transgenic models can be used to investigate the behavior of MSCs and related mechanisms. Such application may further the development of stem cell therapy for tissue damage and other diseases.
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Papait A, Ragni E, Cargnoni A, Vertua E, Romele P, Masserdotti A, Perucca Orfei C, Signoroni PB, Magatti M, Silini AR, De Girolamo L, Parolini O. Comparison of EV-free fraction, EVs, and total secretome of amniotic mesenchymal stromal cells for their immunomodulatory potential: a translational perspective. Front Immunol 2022; 13:960909. [PMID: 36052081 PMCID: PMC9424831 DOI: 10.3389/fimmu.2022.960909] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
Amniotic mesenchymal stromal cells (hAMSCs) have unique immunomodulatory properties demonstrated in vitro and in vivo in various diseases in which the dysregulated immune system plays a major role. The immunomodulatory and pro-regenerative effects of MSCs, among which hAMSCs lie in the bioactive factors they secrete and in their paracrine activity, is well known. The mix of these factors (i.e., secretome) can be either freely secreted or conveyed by extracellular vesicles (EV), thus identifying two components in the cell secretome: EV-free and EV fractions. This study aimed to discern the relative impact of the individual components on the immunomodulatory action of the hAMSC secretome in order to obtain useful information for implementing future therapeutic approaches using immunomodulatory therapies based on the MSC secretome. To this aim, we isolated EVs from the hAMSC secretome (hAMSC-CM) by ultracentrifugation and validated the vesicular product according to the International Society for Extracellular Vesicles (ISEV) criteria. EVs were re-diluted in serum-free medium to maintain the EV concentration initially present in the original CM. We compared the effects of the EV-free and EV fractions with those exerted by hAMSC-CM in toto on the activation and differentiation of immune cell subpopulations belonging to both the innate and adaptive immune systems. We observed that the EV-free fraction, similar to hAMSC-CM in toto, a) decreases the proliferation of activated peripheral blood mononuclear cells (PBMC), b) reduces the polarization of T cells toward inflammatory Th subsets, and induces the induction of regulatory T cells; c) affects monocyte polarization to antigen-presenting cells fostering the acquisition of anti-inflammatory macrophage (M2) markers; and d) reduces the activation of B lymphocytes and their maturation to plasma cells. We observed instead that all investigated EV fractions, when used in the original concentrations, failed to exert any immunomodulatory effect, even though we show that EVs are internalized by various immune cells within PBMC. These findings suggest that the active component able to induce immune regulation, tested at original concentrations, of the hAMSC secretome resides in factors not conveyed in EVs. However, EVs isolated from hAMSC could exert actions on other cell types, as reported by others.
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Affiliation(s)
- Andrea Papait
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, Rome, Italy
| | - Enrico Ragni
- Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS Istituto Ortopedico Galeazzi, Laboratorio di Biotecnologie Applicate all’Ortopedia, Milan, Italy
| | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Elsa Vertua
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Pietro Romele
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Alice Masserdotti
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Carlotta Perucca Orfei
- Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS Istituto Ortopedico Galeazzi, Laboratorio di Biotecnologie Applicate all’Ortopedia, Milan, Italy
| | | | - Marta Magatti
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Antonietta R. Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Laura De Girolamo
- Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS Istituto Ortopedico Galeazzi, Laboratorio di Biotecnologie Applicate all’Ortopedia, Milan, Italy
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, Rome, Italy
- *Correspondence: Ornella Parolini,
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Yu M, Zhou M, Li J, Zong R, Yan Y, Kong L, Zhu Q, Li C. Notch-activated mesenchymal stromal/stem cells enhance the protective effect against acetaminophen-induced acute liver injury by activating AMPK/SIRT1 pathway. Stem Cell Res Ther 2022; 13:318. [PMID: 35842731 PMCID: PMC9288678 DOI: 10.1186/s13287-022-02999-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/22/2022] [Indexed: 12/03/2022] Open
Abstract
Background Notch signaling plays important roles in regulating innate immunity. However, little is known about the role of Notch in mesenchymal stromal/stem cell (MSC)-mediated immunomodulation during liver inflammatory response. Methods Notch activation in human umbilical cord-derived MSCs was performed by a tissue culture plate coated with Notch ligand, recombinant human Jagged1 (JAG1). Mice were given intravenous injection of Notch-activated MSCs after acetaminophen (APAP)-induced acute liver injury. Liver tissues were collected and analyzed by histology and immunohistochemistry. Results MSC administration reduced APAP-induced hepatocellular damage, as manifested by decreased serum ALT levels, intrahepatic macrophage/neutrophil infiltration, hepatocellular apoptosis and proinflammatory mediators. The anti-inflammatory activity and therapeutic effects of MSCs were greatly enhanced by Notch activation via its ligand JAG1. However, Notch2 disruption in MSCs markedly diminished the protective effect of MSCs against APAP-induced acute liver injury, even in the presence of JAG1 pretreatment. Strikingly, Notch-activated MSCs promoted AMP-activated protein kinase (AMPKα) phosphorylation, increased the sirtuins 1 (SIRT1) deacetylase expression, but downregulated spliced X-box-binding protein 1 (XBP1s) expression and consequently reduced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation. Furthermore, SIRT1 disruption or XBP1s overexpression in macrophages exacerbated APAP-triggered liver inflammation and augmented NLRP3/caspase-1 activity in MSC-administrated mice. Mechanistic studies further demonstrated that JAG1-pretreated MSCs activated Notch2/COX2/PGE2 signaling, which in turn induced macrophage AMPK/SIRT1 activation, leading to XBP1s deacetylation and inhibition of NLRP3 activity. Conclusions Activation of Notch2 is required for the ability of MSCs to reduce the severity of APAP-induced liver damage in mice. Our findings underscore a novel molecular insights into MSCs-mediated immunomodulation by activating Notch2/COX2/AMPK/SIRT1 pathway and thus provide a new strategy for the treatment of liver inflammatory diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02999-6.
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Affiliation(s)
- Mengxue Yu
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Min Zhou
- Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jiahui Li
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.,Department of Anatomy and Histology Embryology, Jinzhou Medical University, Jinzhou, China
| | - Ruobin Zong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yufei Yan
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Liangyi Kong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Qiang Zhu
- Children's Hospital of Nanjing Medical University, Nanjing, China.
| | - Changyong Li
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
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Shegos CJ, Chaudhry AF. A narrative review of mesenchymal stem cells effect on osteoarthritis. ANNALS OF JOINT 2022; 7:26. [PMID: 38529128 PMCID: PMC10929318 DOI: 10.21037/aoj-21-16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/27/2021] [Indexed: 03/27/2024]
Abstract
Objective To describe and discuss the purposed mechanism of mesenchymal stem cells (MSCs) and their effect as a potential therapeutic in osteoarthritis (OA). Background OA is a chronic, degenerative joint disease affecting millions worldwide. Traditional management, including physical therapy, anti-inflammatories, intra-articular injections, and surgical procedures are directed towards symptom control rather than disease modification. In light of a better understanding that low-grade inflammation disrupts articular cartilage homeostasis in OA, application of MSCs as a form of regenerative medicine has emerged with the goal to provide symptomatic relief as well as reverse the articular cartilage damage seen in OA. Methods PubMed was searched using terms 'osteoarthritis', 'mesenchymal stem cell', 'regenerative medicine', 'chondrocyte', and 'articular cartilage' available from 2006 through May 2021. Conclusions The use of MSC therapy for articular cartilage regeneration through direct tissue growth, differentiation, and inflammation modulations for the treatment of OA is promising. MSCs migrate to injured sites, inhibit pro-inflammatory pathways, and promote tissue repair by releasing paracrine signals and differentiating into specialized chondrocytes. Multiple clinical trials have displayed a significant improvement in both pain and joint function, inflammatory cell reduction within a joint, and articular cartilage growth as well as patient safety. However, high quality evidence supporting the beneficial role of MSCs is lacking due to the limited number of studies, small populations tested, and the use of various derivatives. Although limited, current evidence suggests MSCs are a potential therapeutic in OA and provides a great foundation for further research.
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