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Li J, Deng T, Zhu S, Xie P, Wang W, Zhou H, Xu C. The SDF-1/CXCR4 axis is involved in adipose-derived stem cell migration. Neurourol Urodyn 2024; 43:2279-2289. [PMID: 39149821 DOI: 10.1002/nau.25571] [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: 12/06/2023] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 08/17/2024]
Abstract
BACKGROUND Intravenous injection of adipose-derived stem cells (ADSCs) can improve the urinary function of stress urinary incontinence (SUI) model rats and C-X-C chemokine receptor type 4 (CXCR4)-positive ADSCs are found in urethral tissues. The CXCR4 ligand stromal cell-derived factor-1 (SDF-1) is highly expressed in urinary incontinence model rats. In this study, we investigated the involvement of the SDF-1/CXCR4 axis in the homing of ADSCs. METHODS ADSCs were isolated from rats and purified. The levels of CXCR4 and CXCR7 were determined by western blot analysis and immunofluorescence assays following stimulation with SDF-1. Hypoxia conditioning was performed to treat the cells in vitro, following which the messenger RNA (mRNA) and protein level of SDF-1, CXCR4, and CXCR7 were estimated. RESULTS We found that CXCR4 and CXCR7 were expressed in ADSCs at passage zero (P0), P1, and P3, and the expression of both increased after SDF-1 stimulation. The level of expression of the mRNAs and proteins of SDF-1, CXCR4, and CXCR7 in ADSCs was higher after hypoxic conditioning. We then knocked down CXCR4 or CXCR7 using small interfering RNAs and found that the mRNA levels of CXCR4 and CXCR7 were considerably downregulated in the si-CXCR4/7-transfected cells. We also found that the SDF-1/CXCR4 axis was required for the migration of ADSCs. The phosphorylation levels of Janus kinase (JAK), protein kinase B (AKT), and extracellular regulated protein kinase significantly increased in SDF-1-stimulated ADSCs. However, the migration of ADSCs was suppressed when the corresponding specific inhibitors were used to block JAK and AKT signaling or silence CXCR4, whereas no significant change was observed in the migratory ability of ADSCs when the ERK pathway was blocked or CXCR7 was silenced. CONCLUSIONS The SDF-1/CXCR4 axis is involved in the migration of ADSCs and may play a role in the migrate of ADSCs in SUI.
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Affiliation(s)
- Jiang Li
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing, China
| | - Tibin Deng
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing, China
| | - Shaojie Zhu
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing, China
| | - Pingbo Xie
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing, China
| | - Wei Wang
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing, China
| | - Hongqing Zhou
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing, China
| | - Chenxiang Xu
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing, China
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Mohammed AN, Kohram F, Lan YW, Li E, Kolesnichenko OA, Kalin TV, Kalinichenko VV. Transplantation of alveolar macrophages improves the efficacy of endothelial progenitor cell therapy in mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2024; 327:L114-L125. [PMID: 38772902 PMCID: PMC11380942 DOI: 10.1152/ajplung.00274.2023] [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: 08/28/2023] [Revised: 04/12/2024] [Accepted: 05/07/2024] [Indexed: 05/23/2024] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a severe complication of preterm births, which develops due to exposure to supplemental oxygen and mechanical ventilation. Published studies demonstrated that the number of endothelial progenitor cells (EPC) is decreased in mouse and human BPD lungs and that adoptive transfer of EPC is an effective approach in reversing the hyperoxia-induced lung damage in mouse model of BPD. Recent advancements in macrophage biology identified the specific subtypes of circulating and resident macrophages mediating the developmental and regenerative functions in the lungs. Several studies reported the successful application of macrophage therapy in accelerating the regenerative capacity of damaged tissues and enhancing the therapeutic efficacy of other transplantable progenitor cells. In the present study, we explored the efficacy of combined cell therapy with EPC and resident alveolar macrophages (rAM) in hyperoxia-induced BPD mouse model. rAM and EPC were purified from neonatal mouse lungs and were used for adoptive transfer to the recipient neonatal mice exposed to hyperoxia. Adoptive transfer of rAM alone did not result in engraftment of donor rAM into the lung tissue but increased the mRNA level and protein concentration of proangiogenic CXCL12 chemokine in recipient mouse lungs. Depletion of rAM by chlodronate-liposomes decreased the retention of donor EPC after their transplantation into hyperoxia-injured lungs. Adoptive transfer of rAM in combination with EPC enhanced the therapeutic efficacy of EPC as evidenced by increased retention of EPC, increased capillary density, improved arterial oxygenation, and alveolarization in hyperoxia-injured lungs. Dual therapy with EPC and rAM has promise in human BPD.NEW & NOTEWORTHY Recent studies demonstrated that transplantation of lung-resident endothelial progenitor cells (EPC) is an effective therapy in mouse model of bronchopulmonary dysplasia (BPD). However, key factors regulating the efficacy of EPC are unknown. Herein, we demonstrate that transplantation of tissue-resident alveolar macrophages (rAM) increases CXCL12 expression in neonatal mouse lungs. rAM are required for retention of donor EPC in hyperoxia-injured lungs. Co-transplantation of rAM and EPC improves the efficacy of EPC therapy in mouse BPD model.
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Affiliation(s)
- Afzaal Nadeem Mohammed
- Department of Child Health, Phoenix Children's Research Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States
| | - Fatemeh Kohram
- Department of Child Health, Phoenix Children's Research Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States
| | - Ying-Wei Lan
- Department of Child Health, Phoenix Children's Research Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States
| | - Enhong Li
- Department of Child Health, Phoenix Children's Research Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States
| | - Olena A Kolesnichenko
- Division of Neonatology and Pulmonary Biology, Cincinnati Children's Research Foundation, Cincinnati, Ohio, United States
| | - Tanya V Kalin
- Department of Child Health, Phoenix Children's Research Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States
| | - Vladimir V Kalinichenko
- Department of Child Health, Phoenix Children's Research Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States
- Division of Neonatology, Phoenix Children's Hospital, Phoenix, Arizona, United States
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Frost OG, Ramkilawan P, Rebbaa A, Stolzing A. A systematic review of lifespan studies in rodents using stem cell transplantations. Ageing Res Rev 2024; 97:102295. [PMID: 38588866 DOI: 10.1016/j.arr.2024.102295] [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: 12/24/2023] [Revised: 03/27/2024] [Accepted: 04/03/2024] [Indexed: 04/10/2024]
Abstract
Organismal aging involves the progressive decline in organ function and increased susceptibility to age-associated diseases. Regardless of its origin, cellular aging is consequently reflected at the level of organ and associated systems dysfunction. Aging of stem cell populations within the body and their decreased ability to self-renew, differentiate, and regenerate damaged tissues, is a key contributor to organismal decline. Based on this, supplementing young stem cells may delay tissue aging, improve frailty and extend health and lifespan. This review investigates studies in rodents using stem cell transplantation from either mice or human donors. The aim is to consolidate available information on the efficacy of stem cell therapies in rodent models and provide insights to guide further research efforts. Out of the 21 studies included in this review, the methodology varied significantly including the lifespan measurement. To enable comparison the median lifespan was calculated using WebPlotDigitizer 4.6 if not provided by the literature. A total of 18 out of 21 studies evidenced significant lifespan extension post stem cell transplant, with 7 studies demonstrating benefits in reduced frailty and other aging complications.
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Affiliation(s)
- Oliver G Frost
- Centre for Biological Engineering, School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough LE11 3TU, UK; SENS Research Foundation, Mountain View, CA 94041, USA
| | | | | | - Alexandra Stolzing
- Centre for Biological Engineering, School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough LE11 3TU, UK.
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Pensado-López A, Ummarino A, Khan S, Guildford A, Allan IU, Santin M, Chevallier N, Varaillon E, Kon E, Allavena P, Torres Andón F. Synthetic peptides of IL-1Ra and HSP70 have anti-inflammatory activity on human primary monocytes and macrophages: Potential treatments for inflammatory diseases. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2024; 55:102719. [PMID: 37977510 DOI: 10.1016/j.nano.2023.102719] [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: 08/22/2023] [Revised: 10/05/2023] [Accepted: 10/23/2023] [Indexed: 11/19/2023]
Abstract
Chronic inflammatory diseases are increasing in developed societies, thus new anti-inflammatory approaches are needed in the clinic. Synthetic peptides complexes can be designed to mimic the activity of anti-inflammatory mediators, in order to alleviate inflammation. Here, we evaluated the anti-inflammatory efficacy of tethered peptides mimicking the interleukin-1 receptor antagonist (IL-1Ra) and the heat-shock protein 70 (HSP70). We tested their biocompatibility and anti-inflammatory activity in vitro in primary human monocytes and differentiated macrophages activated with two different stimuli: the TLR agonists (LPS + IFN-γ) or Pam3CSK4. Our results demonstrate that IL-1Ra and HSP70 synthetic peptides present a satisfactory biocompatible profile and significantly inhibit the secretion of several pro-inflammatory cytokines (IL-6, IL-8, IL-1β and TNFα). We further confirmed their anti-inflammatory activity when peptides were coated on a biocompatible material commonly employed in surgical implants. Overall, our findings support the potential use of IL-1Ra and HSP70 synthetic peptides for the treatment of inflammatory conditions.
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Affiliation(s)
- Alba Pensado-López
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy.
| | - Aldo Ummarino
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, 20089, Milan, Italy.
| | - Sophia Khan
- Tissue Click Ltd, The Knoll Business Centre, Old Shoreham Rd, Hove, BN3 7GS, UK.
| | - Anna Guildford
- Tissue Click Ltd, The Knoll Business Centre, Old Shoreham Rd, Hove, BN3 7GS, UK.
| | - Iain U Allan
- Tissue Click Ltd, The Knoll Business Centre, Old Shoreham Rd, Hove, BN3 7GS, UK.
| | - Matteo Santin
- Centre for Regenerative Medicine and Devices, School of Applied Sciences, University of Brighton, Huxley Building Lewes Road, Brighton BN 24GJ, UK.
| | - Nathalie Chevallier
- IMRB, U955, INSERM, Unite d'Ingenierie et de Therapie Cellulaire-Etablissement Français du Sang, Universite Paris-EST Créteil, 94017 Créteil, France.
| | - Elina Varaillon
- IMRB, U955, INSERM, Unite d'Ingenierie et de Therapie Cellulaire-Etablissement Français du Sang, Universite Paris-EST Créteil, 94017 Créteil, France.
| | - Elizaveta Kon
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, 20089, Milan, Italy.
| | - Paola Allavena
- IRCCS Humanitas Research Hospital, Rozzano, 20089, Milan, Italy.
| | - Fernando Torres Andón
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy; Instituto de Investigación Biomédica de A Coruña (INIBIC), Medical Oncology Unit, Complexo Hospitalario de A Coruña (CHUAC), 15006 A Coruña, Spain.
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Li DY, Li YM, Lv DY, Deng T, Zeng X, You L, Pang QY, Li Y, Zhu BM. Enhanced interaction between genome-edited mesenchymal stem cells and platelets improves wound healing in mice. J Tissue Eng 2024; 15:20417314241268917. [PMID: 39329066 PMCID: PMC11425747 DOI: 10.1177/20417314241268917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 06/26/2024] [Indexed: 09/28/2024] Open
Abstract
Impaired wound healing poses a significant burden on the healthcare system and patients. Stem cell therapy has demonstrated promising potential in the treatment of wounds. However, its clinical application is hindered by the low efficiency of cell homing. In this study, we successfully integrated P-selectin glycoprotein ligand-1 (PSGL-1) into the genome of human adipose-derived mesenchymal stem cells (ADSCs) using a Cas9-AAV6-based genome editing tool platform. Our findings revealed that PSGL-1 knock-in enhanced the binding of ADSCs to platelets and their adhesion to the injured site. Moreover, the intravenous infusion of PSGL-1 -engineered ADSCs (KI-ADSCs) significantly improved the homing efficiency and residence rate at the site of skin lesions in mice. Mechanistically, PSGL-1 knock-in promotes the release of some therapeutic cytokines by activating the canonical WNT/β-catenin signaling pathway and accelerates the healing of wounds by promoting angiogenesis, re-epithelialization, and granulation tissue formation at the wound site. This study provides a novel strategy to simultaneously address the problem of poor migration and adhesion of mesenchymal stem cells (MSCs).
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Affiliation(s)
- De-Yong Li
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yu-Meng Li
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dan-Yi Lv
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tian Deng
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xin Zeng
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Lu You
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qiu-Yu Pang
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yi Li
- Core Facilities of West China Hospital, Sichuan University, Chengdu, China
| | - Bing-Mei Zhu
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Wang Y, Gao T, Wang B. Application of mesenchymal stem cells for anti-senescence and clinical challenges. Stem Cell Res Ther 2023; 14:260. [PMID: 37726805 PMCID: PMC10510299 DOI: 10.1186/s13287-023-03497-z] [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: 07/25/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023] Open
Abstract
Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related diseases. Although some methods have been identified to partly delay senescence, such as strengthening exercise, restricting diet, and some drugs, these only slow down the process of senescence and cannot fundamentally delay or even reverse senescence. Stem cell-based therapy is expected to be a potential effective way to alleviate or cure senescence-related disorders in the coming future. Mesenchymal stromal cells (MSCs) are the most widely used cell type in treating various diseases due to their potentials of self-replication and multidirectional differentiation, paracrine action, and immunoregulatory effects. Some biological characteristics of MSCs can be well targeted at the pathological features of aging. Therefore, MSC-based therapy is also a promising strategy to combat senescence-related diseases. Here we review the recent progresses of MSC-based therapies in the research of age-related diseases and the challenges in clinical application, proving further insight and reference for broad application prospects of MSCs in effectively combating senesce in the future.
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Affiliation(s)
- Yaping Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China
| | - Tianyun Gao
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China.
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Chiu YH, Liang YH, Hwang JJ, Wang HS. IL-1β stimulated human umbilical cord mesenchymal stem cells ameliorate rheumatoid arthritis via inducing apoptosis of fibroblast-like synoviocytes. Sci Rep 2023; 13:15344. [PMID: 37714911 PMCID: PMC10504325 DOI: 10.1038/s41598-023-42585-1] [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: 03/07/2023] [Accepted: 09/12/2023] [Indexed: 09/17/2023] Open
Abstract
Rheumatoid arthritis (RA) is characterized by synovial proliferation and lymphocyte accumulation leading to progressive damage of the periarticular bone and the articular cartilage. The hyperplasia of the synovial intima lining mainly consists of fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA) which exhibit apoptosis-resistance, hyper-proliferation, and high invasiveness. The therapeutic efficacy of mesenchymal stem cells (MSCs) treatment in RA has been shown to be due to its immuno-regulatory ability. However, the exact factors and mechanisms involved in MSCs treatment in RA remain unclear. In this study, TRAIL receptor-Death receptor 4 (DR4), DR5, and LFA-1 ligand-intercellular adhesion molecule-1 (ICAM-1) were upregulated in IL-1β-stimulated HFLS-RA. We demonstrated that the total cell number of IL-1β-stimulated hUCMSCs adhering to IL-1β-stimulated HFLA-RA increased via LFA-1/ICAM-1 interaction. Direct co-culture of IL-1β-stimulated hUCMSCs with IL-1β-stimulated HFLS-RA increased the apoptosis of HFLS-RA. RA symptoms in the CIA mouse model improved after administration of IL-1β-stimulated hUCMSCs. In conclusion, IL-1β-stimulated hUCMSCs adhering to HFLS-RA occurred via LFA-1/ICAM-1 interaction, apoptosis of HFLS-RA was induced via TRAIL/DR4, DR5 contact, and RA symptoms and inflammation were significantly improved in a CIA mouse model. The results of this study suggest that IL-1β-stimulated hUCMSCs have therapeutic potential in RA treatment.
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Affiliation(s)
- Yun-Hsuan Chiu
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Peitou, Taipei, 112, Taiwan, ROC
| | - Ya-Han Liang
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Peitou, Taipei, 112, Taiwan, ROC
| | - Jeng-Jong Hwang
- Department of Medical Imaging, Chung Shan Medical University Hospital affiliated with Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, 402, Taiwan, ROC
| | - Hwai-Shi Wang
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Peitou, Taipei, 112, Taiwan, ROC.
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Dantas JR, Araujo DB, Silva KR, Souto DL, Pereira MDFC, Raggio LR, Claudio-da Silva C, Couri CE, Maiolino A, Rebellato CLK, Daga DR, Senegaglia AC, Brofman PRS, Baptista LS, Oliveira JEPD, Zajdenverg L, Rodacki M. Adipose Tissue-Derived Stromal/Stem Cells Transplantation with Cholecalciferol Supplementation in Recent-Onset Type 1 Diabetes Patients: Twelve Months Follow-Up. Horm Metab Res 2023; 55:536-545. [PMID: 37192655 DOI: 10.1055/a-2094-1039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
To evaluate safety and therapeutic effect along 12 months of allogenic adipose tissue-derived stromal/stem cells (ASCs) transplantation with cholecalciferol (VITD) in patients with recent-onset type 1 diabetes (T1D). Prospective, phase II, open trial, pilot study in which patients with recent onset T1D received ASCs (1xKgx106 cells) and VITD 2000UI/day for 12 months (group 1) and were compared to controls with standard insulin therapy (group 2). Adverse events, C-peptide area under the curve (CPAUC), insulin dose, HbA1c and frequency of FoxP3+ in CD4+ or CD8+ T-cells(flow cytometry) were evaluated at baseline(T0), after 3(T3), 6(T6) and 12 months(T12). Eleven patients completed follow up (7:group 1;4:group 2). Group 1 had lower insulin requirement at T3(0.24±0.18vs0.53±0.23UI/kg,p=0.04), T6(0.24±0.15vs0.66±0.33 UI/kg,p=0.04) and T12(0.39±0.15vs0.74±0.29 UI/Kg,p=0.04).HbA1c was lower at T6 (50.57±8.56vs72.25±10.34 mmol/mol,p=0.01), without differences at T12 (57.14±11.98 in group 1 vs. 73.5±14.57 mmol/min in group 2, p=0.16). CPAUC was not significantly different between groups at T0(p=0.07), higher in group 1 at T3(p=0.04) and T6(p=0.006), but similar at T12(p=0.23). IDAA1c was significantly lower in group 1 than group 2 at T3,T6 and T12 (p=0.006, 0.006 and 0.042, respectively). IDDA1c was inversely correlated to FoxP3 expression in CD4 and CD8+ T cells at T6 (p<0.001 and p=0.01, respectively). In group 1, one patient had recurrence of a benign teratoma that was surgically removed, not associated to the intervention. ASCs with VITD without immunosuppression were safe and associated lower insulin requirements, better glycemic control, and transient better pancreatic function in recent onset T1D, but the potential benefits were not sustained.
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Affiliation(s)
- Joana R Dantas
- Nutrology and Diabetes Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Debora Batista Araujo
- Nutrology and Diabetes Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Karina Ribeiro Silva
- Laboratory of Tissue Bioengineering, Instituto Nacional de Metrologia Qualidade e Tecnologia Campus de Xerem, Duque de Caxias, Brazil
- Histology and Embryology Departament, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Debora Lopes Souto
- Nutrology and Diabetes Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Luiz Ronir Raggio
- Institute of Public Health Studies, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Carlos Eduardo Couri
- Internal Medicine, Universidade de São Paulo Faculdade de Medicina de Ribeirão Preto, Ribeirao Preto, Brazil
| | - Angelo Maiolino
- Hematology Department, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Debora Regina Daga
- Core Cell Technology, Pontifical Catholic University of Parana, Curitiba, Brazil
| | | | | | - Leandra S Baptista
- Laboratory of Tissue Bioengineering, Instituto Nacional de Metrologia Qualidade e Tecnologia Campus de Xerem, Duque de Caxias, Brazil
- Center for Biological Research (Numpex-Bio), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Lenita Zajdenverg
- Nutrology and Diabetes Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Melanie Rodacki
- Nutrology and Diabetes Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Ashraf M, Tipparaju SM, Kim JW, Xuan W. Chemokine/ITGA4 Interaction Directs iPSC-Derived Myogenic Progenitor Migration to Injury Sites in Aging Muscle for Regeneration. Cells 2023; 12:1837. [PMID: 37508502 PMCID: PMC10378040 DOI: 10.3390/cells12141837] [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: 06/09/2023] [Revised: 07/09/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
The failure of muscle to repair after injury during aging may be a major contributor to muscle mass loss. We recently generated muscle progenitor cells (MPCs) from human-induced pluripotent stem-cell (iPSC) cell lines using small molecules, CHIR99021 and Givinostat (Givi-MPCs) sequentially. Here, we test whether the chemokines overexpressed in injured endothelial cells direct MPC migration to the site by binding to their receptor, ITGA4. ITGA4 was heavily expressed in Givi-MPCs. To study the effects on the mobilization of Givi-MPCs, ITGA4 was knocked down by an ITGA4 shRNA lentiviral vector. With and without ITGA4 knocked down, cell migration in vitro and cell mobilization in vivo using aged NOD scid gamma (NSG) mice and mdx/scid mice were analyzed. The migration of shITGA4-Givi-MPCs was significantly impaired, as shown in a wound-healing assay. The knockdown of ITGA4 impaired the migration of Givi-MPCs towards human aortic endothelial cells (HAECs), in which CX3CL1 and VCAM-1 were up-regulated by the treatment of TNF-α compared with scramble ones using a transwell system. MPCs expressing ITGA4 sensed chemokines secreted by endothelial cells at the injury site as a chemoattracting signal to migrate to the injured muscle. The mobilization of Givi-MPCs was mediated by the ligand-receptor interaction, which facilitated their engraftment for repairing the sarcopenic muscle with injury.
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SDF-1α-Releasing Microspheres Effectively Extend Stem Cell Homing after Myocardial Infarction. Biomedicines 2023; 11:biomedicines11020343. [PMID: 36830880 PMCID: PMC9953248 DOI: 10.3390/biomedicines11020343] [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: 01/05/2023] [Revised: 01/20/2023] [Accepted: 01/24/2023] [Indexed: 01/27/2023] Open
Abstract
Ischemic heart disease (IHD) is one of the main focuses in today's healthcare due to its implications and complications, and it is predicted to be increasing in prevalence due to the ageing population. Although the conventional pharmacological and interventional methods for the treatment of IHD presents with success in the clinical setting, the long-term complications of cardiac insufficiency are on a continual incline as a result of post-infarction remodeling of the cardiac tissue. The migration and involvement of stem cells to the cardiac muscle, followed by differentiation into cardiac myocytes, has been proven to be the natural process, though at a slow rate. SDF-1α is a novel candidate to mobilize stem cells homing to the ischemic heart. Endogenous SDF-1α levels are elevated after myocardial infarction, but their presence gradually decreases after approximately seven days. Additional administration of SDF-1α-releasing microspheres could be a tool for the extension of the time the stem cells are in the cardiac tissue after myocardial infarction. This, in turn, could constitute a novel therapy for more efficient regeneration of the heart muscle after injury. Through this practical study, it has been shown that the controlled release of SDF-1α from biodegradable microspheres into the pericardial sac fourteen days after myocardial infarction increases the concentration of exogenous SDF-1α, which persists in the tissue much longer than the level of endogenous SDF-1α. In addition, administration of SDF-1α-releasing microspheres increased the expression of the factors potentially involved in the involvement and retention of myocardial stem cells, which constitutes vascular endothelial growth factor A (VEGFA), stem cell factor (SCF), and vascular cell adhesion molecules (VCAMs) at the site of damaged tissue. This exhibits the possibility of combating the basic limitations of cell therapy, including ineffective stem cell implantation and the ability to induce the migration of endogenous stem cells to the ischemic cardiac tissue and promote heart repair.
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11
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Petinati N, Shipounova I, Sats N, Dorofeeva A, Sadovskaya A, Kapranov N, Tkachuk Y, Bondarenko A, Muravskaya M, Kotsky M, Kaplanskaya I, Vasilieva T, Drize N. Multipotent Mesenchymal Stromal Cells from Porcine Bone Marrow, Implanted under the Kidney Capsule, form an Ectopic Focus Containing Bone, Hematopoietic Stromal Microenvironment, and Muscles. Cells 2023; 12:268. [PMID: 36672203 PMCID: PMC9857022 DOI: 10.3390/cells12020268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/02/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Multipotent mesenchymal stromal cells (MSCs) are an object of intense investigation due to their therapeutic potential. MSCs have been well studied in vitro, while their fate after implantation in vivo has been poorly analyzed. We studied the properties of MSCs from the bone marrow (BM-MSC) before and after implantation under the renal capsule using a mini pig model. Autologous BM-MSCs were implanted under the kidney capsule. After 2.5 months, ectopic foci containing bones, foci of ectopic hematopoiesis, bone marrow stromal cells and muscle cells formed. Small pieces of the implant were cultivated as a whole. The cells that migrated out from these implants were cultured, cloned, analyzed and were proven to meet the most of criteria for MSCs, therefore, they are designated as MSCs from the implant-IM-MSCs. The IM-MSC population demonstrated high proliferative potential, similar to BM-MSCs. IM-MSC clones did not respond to adipogenic differentiation inductors: 33% of clones did not differentiate, and 67% differentiated toward an osteogenic lineage. The BM-MSCs revealed functional heterogeneity after implantation under the renal capsule. The BM-MSC population consists of mesenchymal precursor cells of various degrees of differentiation, including stem cells. These newly discovered properties of mini pig BM-MSCs reveal new possibilities in terms of their manipulation.
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Affiliation(s)
- Nataliya Petinati
- Laboratory for Physiology of Hematopoiesis, National Medical Research Center for Hematology, Ministry of Health of the Russian Federation, 125167 Moscow, Russia
| | - Irina Shipounova
- Laboratory for Physiology of Hematopoiesis, National Medical Research Center for Hematology, Ministry of Health of the Russian Federation, 125167 Moscow, Russia
| | - Natalia Sats
- Laboratory for Physiology of Hematopoiesis, National Medical Research Center for Hematology, Ministry of Health of the Russian Federation, 125167 Moscow, Russia
| | - Alena Dorofeeva
- Laboratory for Physiology of Hematopoiesis, National Medical Research Center for Hematology, Ministry of Health of the Russian Federation, 125167 Moscow, Russia
| | - Alexandra Sadovskaya
- Laboratory for Physiology of Hematopoiesis, National Medical Research Center for Hematology, Ministry of Health of the Russian Federation, 125167 Moscow, Russia
- Department of Immunology, Faculty of Biology, Federal State Budget Educational Institution of Higher Education M.V. Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Nikolay Kapranov
- Laboratory for Physiology of Hematopoiesis, National Medical Research Center for Hematology, Ministry of Health of the Russian Federation, 125167 Moscow, Russia
| | - Yulia Tkachuk
- Bioclinic for Working with Animals, Federal State Budgetary Scientific Institution Izmerov Research Institute of Occupational Health, 105275 Moscow, Russia
| | - Anatoliy Bondarenko
- Bioclinic for Working with Animals, Federal State Budgetary Scientific Institution Izmerov Research Institute of Occupational Health, 105275 Moscow, Russia
| | - Margarita Muravskaya
- Bioclinic for Working with Animals, Federal State Budgetary Scientific Institution Izmerov Research Institute of Occupational Health, 105275 Moscow, Russia
| | - Michail Kotsky
- Bioclinic for Working with Animals, Federal State Budgetary Scientific Institution Izmerov Research Institute of Occupational Health, 105275 Moscow, Russia
| | - Irina Kaplanskaya
- MNIOI Them. P.A. Herzen—Branch of the Federal State Budgetary Institution “NMITs Radiology” of the Ministry of Health of Russia, Department of Pathomorphology, 125284 Moscow, Russia
| | - Tamara Vasilieva
- Department of Cell Biology, Faculty of Biology, Federal State Budget Educational Institution of Higher Education M.V. Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Nina Drize
- Laboratory for Physiology of Hematopoiesis, National Medical Research Center for Hematology, Ministry of Health of the Russian Federation, 125167 Moscow, Russia
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12
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Controlled Release of Encapsuled Stromal-Derived Factor 1α Improves Bone Marrow Mesenchymal Stromal Cells Migration. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 9:bioengineering9120754. [PMID: 36550960 PMCID: PMC9774977 DOI: 10.3390/bioengineering9120754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 11/18/2022] [Accepted: 11/29/2022] [Indexed: 12/04/2022]
Abstract
Stem cell treatment is a promising method of therapy for the group of patients whose conventional options for treatment have been limited or rejected. Stem cells have the potential to repair, replace, restore and regenerate cells. Moreover, their proliferation level is high. Owing to these features, they can be used in the treatment of numerous diseases, such as cancer, lung diseases or ischemic heart diseases. In recent years, stem cell therapy has greatly developed, shedding light on stromal-derived factor 1α (SDF-1α). SDF-1α is a mobilizing chemokine for application of endogenous stem cells to injury sites. Unfortunately, SDF-1α presented short-term results in stem cell treatment trials. Considering the tremendous benefits of this therapy, we developed biodegradable polymeric microspheres for the release of SDF-1α in a controlled and long-lasting manner. The microspheres were designed from poly(L-lactide/glycolide/trimethylene carbonate) (PLA/GA/TMC). The effect of controlled release of SDF-1α from microspheres was investigated on the migration level of bone marrow Mesenchymal Stromal Cells (bmMSCs) derived from a pig. The study showed that SDF-1α, released from the microspheres, is more efficient at attracting bmMSCs than SDF-1α alone. This may enable the controlled delivery of selected and labeled MSCs to the destination in the future.
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13
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Li Y, Tan Z, Zhang J, Mu J, Wu H. Physical and Chemical Properties, Biosafety Evaluation, and Effects of Nano Natural Deer Bone Meal on Bone Marrow Mesenchymal Stem Cells. Front Bioeng Biotechnol 2022; 10:891765. [PMID: 35910014 PMCID: PMC9335367 DOI: 10.3389/fbioe.2022.891765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
At present, bone-based products are abundant, and the main sources are bovine bone and pig bone, but there are few studies on the development of deer bone as a bone repair material. Deer bone has important osteogenic effects in the theory of traditional Chinese medicine. It is rich in protein, ossein, and a variety of trace elements, with the effect of strengthening tendons and bones. Nanomaterials and their application in the repair of bone defects have become a research hotspot in bone tissue engineering. In this study, nano-deer bone meal (nBM), nano-calcined deer bone meal, and nano-demineralized bone matrix were successfully prepared. It was found that the Ca/P ratio in deer bone was significantly higher than that in cow bone and human bone tissue, and deer bone contained beneficial trace elements, such as potassium, iron, selenium, and zinc, which were not found in cow bone. The three kinds of deer bone powders prepared in this study had good biocompatibility and met the implantation standards of medical biomaterials. Cell function studies showed that compared with other bone powders, due to the presence of organic active ingredients and inorganic calcium and phosphate salts, nBM had excellent performance in the proliferation, adhesion, migration, and differentiation of bone marrow mesenchymal stem cells. These findings indicate that nBM can be used as a potential osteoinductive active nanomaterial to enhance bone tissue engineering scaffolds with certain application prospects.
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14
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Canjuga D, Steinle H, Mayer J, Uhde AK, Klein G, Wendel HP, Schlensak C, Avci-Adali M. Homing of mRNA-Modified Endothelial Progenitor Cells to Inflamed Endothelium. Pharmaceutics 2022; 14:pharmaceutics14061194. [PMID: 35745767 PMCID: PMC9229815 DOI: 10.3390/pharmaceutics14061194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/28/2022] [Accepted: 05/30/2022] [Indexed: 01/25/2023] Open
Abstract
Endothelial progenitor cells (EPCs) are one of the most important stem cells for the neovascularization of tissues damaged by ischemic diseases such as myocardial infarction, ischemic stroke, or critical limb ischemia. However, their low homing efficiency in the treatment of ischemic tissues limits their potential clinical applications. The use of synthetic messenger RNA (mRNA) for cell engineering represents a novel and promising technology for the modulation of cell behavior and tissue regeneration. To improve the therapeutic potential of EPCs, in this study, murine EPCs were engineered with synthetic mRNAs encoding C-X-C chemokine receptor 4 (CXCR4) and P-selectin glycoprotein ligand 1 (PSGL-1) to increase the homing and migration efficiency of EPCs to inflamed endothelium. Flow cytometric measurements revealed that the transfection of EPCs with CXCR4 and PSGL-1 mRNA resulted in increased expressions of CXCR4 and PSGL-1 on the cell surface compared with the unmodified EPCs. The transfection of EPCs with mRNAs did not affect cell viability. CXCR4-mRNA-modified EPCs showed significantly higher migration potential than unmodified cells in a chemotactic migration assay. The binding strength of the EPCs to inflamed endothelium was determined with single-cell atomic force microscopy (AFM). This showed that the mRNA-modified EPCs required a three-fold higher detachment force to be released from the TNF-α-activated endothelium than unmodified EPCs. Furthermore, in a dynamic flow model, significantly increased binding of the mRNA-modified EPCs to inflamed endothelium was detected. This study showed that the engineering of EPCs with homing factors encoding synthetic mRNAs increases the homing and migration potentials of these stem cells to inflamed endothelium. Thus, this strategy represents a promising strategy to increase the therapeutic potential of EPCs for the treatment of ischemic tissues.
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Affiliation(s)
- Denis Canjuga
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Heidrun Steinle
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Jana Mayer
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Ann-Kristin Uhde
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Gerd Klein
- Center for Medical Research, Department of Medicine II, University of Tuebingen, Waldhörnlestraße 22, 72072 Tuebingen, Germany;
| | - Hans Peter Wendel
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Christian Schlensak
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Meltem Avci-Adali
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
- Correspondence: ; Tel.: +49-7071-29-86605; Fax: +49-7071-29-3617
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15
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Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors. Nat Cell Biol 2022; 24:659-671. [PMID: 35550611 PMCID: PMC9106586 DOI: 10.1038/s41556-022-00899-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 03/11/2022] [Indexed: 12/11/2022]
Abstract
Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host–graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury. In this study, the authors report that pluripotent stem cell-derived ventricular progenitors target loss of myocardium and fibrotic scarring to promote heart regeneration, thus offering new potential therapeutic strategies for heart injury.
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16
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To Explore the Stem Cells Homing to GBM: The Rise to the Occasion. Biomedicines 2022; 10:biomedicines10050986. [PMID: 35625723 PMCID: PMC9138893 DOI: 10.3390/biomedicines10050986] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/20/2022] [Accepted: 04/20/2022] [Indexed: 12/13/2022] Open
Abstract
Multiple efforts are currently underway to develop targeted therapeutic deliveries to the site of glioblastoma progression. The use of carriers represents advancement in the delivery of various therapeutic agents as a new approach in neuro-oncology. Mesenchymal stem cells (MSCs) and neural stem cells (NSCs) are used because of their capability in migrating and delivering therapeutic payloads to tumors. Two of the main properties that carrier cells should possess are their ability to specifically migrate from the bloodstream and low immunogenicity. In this article, we also compared the morphological and molecular features of each type of stem cell that underlie their migration capacity to glioblastoma. Thus, the major focus of the current review is on proteins and lipid molecules that are released by GBM to attract stem cells.
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17
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022; 14:1-40. [PMID: 35126826 PMCID: PMC8788183 DOI: 10.4252/wjsc.v14.i1.1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/02/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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18
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022. [PMID: 35126826 DOI: 10.4252/wjsc.v14.i1.1]] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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19
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Habib SAH, Alalawy AI, Saad EA, El-Sadda RR. Biochemical and histopathological evaluations of chronic renal failure rats treated with pluripotent human stem cells. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e20089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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20
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Kalia N. A historical review of experimental imaging of the beating heart coronary microcirculation in vivo. J Anat 2021; 242:3-16. [PMID: 34905637 PMCID: PMC9773169 DOI: 10.1111/joa.13611] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/25/2021] [Accepted: 12/03/2021] [Indexed: 12/25/2022] Open
Abstract
Following a myocardial infarction (MI), the prognosis of patients is highly dependent upon the re-establishment of perfusion not only in the occluded coronary artery, but also within the coronary microcirculation. However, our fundamental understanding of the pathophysiology of the tiniest blood vessels of the heart is limited primarily because no current clinical imaging tools can directly visualise them. Moreover, in vivo experimental studies of the beating heart using intravital imaging have also been hampered due to obvious difficulties related to significant inherent contractile motion, movement of the heart brought about by nearby lungs and its location in an anatomically challenging position for microscopy. However, recent advances in microscopy techniques, and the development of fluorescent reporter mice and fluorescently conjugated antibodies allowing visualisation of vascular structures, thromboinflammatory cells and blood flow, have allowed us to overcome some of these challenges and increase our basic understanding of cardiac microvascular pathophysiology. In this review, the elegant attempts of the pioneers in intravital imaging of the beating heart will be discussed, which focussed on providing new insights into the anatomy and physiology of the healthy heart microvessels. The reviews end with the more recent studies that focussed on disease pathology and increasing our understanding of myocardial thromboinflammatory cell recruitment and flow disturbances, particularly in the setting of diseases such as MI.
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Affiliation(s)
- Neena Kalia
- Microcirculation Research GroupInstitute of Cardiovascular SciencesCollege of Medical and Dental SciencesUniversity of BirminghamBirminghamUK
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21
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Bidkhori HR, Bahrami AR, Farshchian M, Heirani-Tabasi A, Mirahmadi M, Hasanzadeh H, Ahmadiankia N, Faridhosseini R, Dastpak M, Shabgah AG, Matin MM. Mesenchymal Stem/Stromal Cells Overexpressing CXCR4 R334X Revealed Enhanced Migration: A Lesson Learned from the Pathogenesis of WHIM Syndrome. Cell Transplant 2021; 30:9636897211054498. [PMID: 34807749 PMCID: PMC8647223 DOI: 10.1177/09636897211054498] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
C-X-C chemokine receptor type 4 (CXCR4), initially recognized as a co-receptor
for HIV, contributes to several disorders, including the WHIM (Warts,
Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome. CXCR4 binds to
its ligand SDF-1 to make an axis involved in the homing property of stem cells.
This study aimed to employ WHIM syndrome pathogenesis as an inspirational
approach to reinforce cell therapies. Wild type and WHIM-type variants of the
CXCR4 gene were chemically synthesized and cloned in the
pCDH-513B-1 lentiviral vector. Molecular cloning of the synthetic genes was
confirmed by DNA sequencing, and expression of both types of CXCR4 at the
protein level was confirmed by western blotting in HEK293T cells. Human
adipose-derived mesenchymal stem cells (Ad-MSCs) were isolated, characterized,
and subjected to lentiviral transduction with Wild type and WHIM-type variants
of CXCR4. The presence of copGFP-positive MSCs confirmed the
high efficiency of transduction. The migration ability of both groups of
transduced cells was then assessed by transwell migration assay in the presence
or absence of a CXCR4-blocking agent. Our qRT-PCR results showed overexpression
of CXCR4 at mRNA level in both groups of transduced MSCs, and
expression of WHIM-type CXCR4 was significantly higher than
Wild type CXCR4 (P<0.05). Our results
indicated that the migration of genetically modified MSCs expressing WHIM-type
CXCR4 had significantly enhanced towards SDF1 in comparison with Wild type CXCR4
(P<0.05), while it was reduced after treatment with
CXCR4 antagonist. These data suggest that overexpression of WHIM-type CXCR4
could lead to enhanced and sustained expression of CXCR4 on human MSCs, which
would increase their homing capability; hence it might be an appropriate
strategy to improve the efficiency of cell-based therapies.
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Affiliation(s)
- Hamid Reza Bidkhori
- Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad, Iran.,Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Ahmad Reza Bahrami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.,Industrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Moein Farshchian
- Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
| | - Asieh Heirani-Tabasi
- Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
| | - Mahdi Mirahmadi
- Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
| | - Halimeh Hasanzadeh
- Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
| | | | - Reza Faridhosseini
- Department of Immunology, Mashhad Universityof Medical Sciences, Mashhad, Iran
| | - Mahtab Dastpak
- Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
| | | | - Maryam M Matin
- Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad, Iran.,Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.,Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
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22
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Arjmand B, Abedi M, Arabi M, Alavi-Moghadam S, Rezaei-Tavirani M, Hadavandkhani M, Tayanloo-Beik A, Kordi R, Roudsari PP, Larijani B. Regenerative Medicine for the Treatment of Ischemic Heart Disease; Status and Future Perspectives. Front Cell Dev Biol 2021; 9:704903. [PMID: 34568321 PMCID: PMC8461329 DOI: 10.3389/fcell.2021.704903] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/19/2021] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular disease is now the leading cause of adult death in the world. According to new estimates from the World Health Organization, myocardial infarction (MI) is responsible for four out of every five deaths due to cardiovascular disease. Conventional treatments of MI are taking aspirin and nitroglycerin as intermediate treatments and injecting antithrombotic agents within the first 3 h after MI. Coronary artery bypass grafting and percutaneous coronary intervention are the most common long term treatments. Since none of these interventions will fully regenerate the infarcted myocardium, there is value in pursuing more innovative therapeutic approaches. Regenerative medicine is an innovative interdisciplinary method for rebuilding, replacing, or repairing the missed part of different organs in the body, as similar as possible to the primary structure. In recent years, regenerative medicine has been widely utilized as a treatment for ischemic heart disease (one of the most fatal factors around the world) to repair the lost part of the heart by using stem cells. Here, the development of mesenchymal stem cells causes a breakthrough in the treatment of different cardiovascular diseases. They are easily obtainable from different sources, and expanded and enriched easily, with no need for immunosuppressing agents before transplantation, and fewer possibilities of genetic abnormality accompany them through multiple passages. The production of new cardiomyocytes can result from the transplantation of different types of stem cells. Accordingly, due to its remarkable benefits, stem cell therapy has received attention in recent years as it provides a drug-free and surgical treatment for patients and encourages a more safe and feasible cardiac repair. Although different clinical trials have reported on the promising benefits of stem cell therapy, there is still uncertainty about its mechanism of action. It is important to conduct different preclinical and clinical studies to explore the exact mechanism of action of the cells. After reviewing the pathophysiology of MI, this study addresses the role of tissue regeneration using various materials, including different types of stem cells. It proves some appropriate data about the importance of ethical problems, which leads to future perspectives on this scientific method.
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Affiliation(s)
- Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Abedi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Arabi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mahdieh Hadavandkhani
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Kordi
- Sports Medicine Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Peyvand Parhizkar Roudsari
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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23
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Transcriptional Profile of Cytokines, Regulatory Mediators and TLR in Mesenchymal Stromal Cells after Inflammatory Signaling and Cell-Passaging. Int J Mol Sci 2021; 22:ijms22147309. [PMID: 34298927 PMCID: PMC8306573 DOI: 10.3390/ijms22147309] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 12/13/2022] Open
Abstract
Adult human subcutaneous adipose tissue (AT) harbors a rich population of mesenchymal stromal cells (MSCs) that are of interest for tissue repair. For this purpose, it is of utmost importance to determine the response of AT-MSCs to proliferative and inflammatory signals within the damaged tissue. We have characterized the transcriptional profile of cytokines, regulatory mediators and Toll-like receptors (TLR) relevant to the response of MSCs. AT-MSCs constitutively present a distinct profile for each gene and differentially responded to inflammation and cell-passaging. Inflammation leads to an upregulation of IL-6, IL-8, IL-1β, TNFα and CCL5 cytokine expression. Inflammation and cell-passaging increased the expression of HGF, IDO1, PTGS1, PTGS2 and TGFβ. The expression of the TLR pattern was differentially modulated with TLR 1, 2, 3, 4, 9 and 10 being increased, whereas TLR 5 and 6 downregulated. Functional enrichment analysis demonstrated a complex interplay between cytokines, TLR and regulatory mediators central for tissue repair. This profiling highlights that following a combination of inflammatory and proliferative signals, the sensitivity and responsive capacity of AT-MSCs may be significantly modified. Understanding these transcriptional changes may help the development of novel therapeutic approaches.
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24
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Dantas JR, Araújo DB, Silva KR, Souto DL, de Fátima Carvalho Pereira M, Luiz RR, Dos Santos Mantuano M, Claudio-da-Silva C, Gabbay MAL, Dib SA, Couri CEB, Maiolino A, Rebelatto CLK, Daga DR, Senegaglia AC, Brofman PRS, Baptista LS, de Oliveira JEP, Zajdenverg L, Rodacki M. Adipose tissue-derived stromal/stem cells + cholecalciferol: a pilot study in recent-onset type 1 diabetes patients. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:342-351. [PMID: 33939911 PMCID: PMC10065343 DOI: 10.20945/2359-3997000000368] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Objective Adipose tissue-derived stromal/stem cells (ASCs) and vitamin D have immunomodulatory actions that could be useful for type 1 diabetes (T1D). We aimed in this study to investigate the safety and efficacy of ASCs + daily cholecalciferol (VIT D) for 6 months in patients with recent-onset T1D. Methods In this prospective, dual-center, open trial, patients with recent onset T1D received one dose of allogenic ASC (1 × 106 cells/kg) and cholecalciferol 2,000 UI/day for 6 months (group 1). They were compared to patients who received chol-ecalciferol (group 2) and standard treatment (group 3). Adverse events were recorded; C-peptide (CP), insulin dose and HbA1c were measured at baseline (T0), after 3 (T3) and 6 months (T6). Results In group 1 (n = 7), adverse events included transient headache (all), mild local reactions (all), tachycardia (n = 4), abdominal cramps (n = 1), thrombophlebitis (n = 4), scotomas (n = 2), and central retinal vein occlusion at T3 (n = 1, resolution at T6). Group 1 had an increase in basal CP (p = 0.018; mean: 40.41+/-40.79 %), without changes in stimulated CP after mixed meal (p = 0.62), from T0 to T6. Basal CP remained stable in groups 2 and 3 (p = 0.58 and p = 0.116, respectively). Group 1 had small insulin requirements (0.31+/- 0.26 UI/kg) without changes at T6 (p = 0.44) and HbA1c decline (p = 0.01). At T6, all patients (100%; n = 7) in group 1 were in honeymoon vs 75% (n = 3/4) and 50% (n = 3/6) in groups 2 and 3, p = 0.01. Conclusion Allogenic ASC + VIT D without immunosuppression was safe and might have a role in the preservation of β-cells in patients with recent-onset T1D. ClinicalTrials.gov: NCT03920397.
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Affiliation(s)
- Joana Rodrigues Dantas
- Departamento de Nutrologia e Diabetes, Universidade Federal do Rio de Janeiro, RJ, Brasil
| | - Débora Batista Araújo
- Departamento de Nutrologia e Diabetes, Universidade Federal do Rio de Janeiro, RJ, Brasil
| | - Karina Ribeiro Silva
- Laboratório de Bioengenharia de Tecidos, Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | - Débora Lopes Souto
- Departamento de Nutrologia e Diabetes, Universidade Federal do Rio de Janeiro, RJ, Brasil,
| | | | - Ronir Raggio Luiz
- Instituto de Estudos de Saúde Pública, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | | | - Cesar Claudio-da-Silva
- Departamento de Cirurgia Plástica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | | | | | | | - Angelo Maiolino
- Departamento de Hematologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | | | - Débora Regina Daga
- Core Cell Technology, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brasil
| | | | | | - Leandra S Baptista
- Centro Multidisciplinar de Pesquisas Biológicas (Numpex-Bio), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil; Laboratório de Bioengenharia de Tecidos, Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro), Rio de Janeiro, RJ, Brasil
| | | | - Lenita Zajdenverg
- Departamento de Nutrologia e Diabetes, Universidade Federal do Rio de Janeiro, RJ, Brasil
| | - Melanie Rodacki
- Departamento de Nutrologia e Diabetes, Universidade Federal do Rio de Janeiro, RJ, Brasil
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25
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Marsico G, Martin‐Saldaña S, Pandit A. Therapeutic Biomaterial Approaches to Alleviate Chronic Limb Threatening Ischemia. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003119. [PMID: 33854887 PMCID: PMC8025020 DOI: 10.1002/advs.202003119] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/24/2020] [Indexed: 05/14/2023]
Abstract
Chronic limb threatening ischemia (CLTI) is a severe condition defined by the blockage of arteries in the lower extremities that leads to the degeneration of blood vessels and is characterized by the formation of non-healing ulcers and necrosis. The gold standard therapies such as bypass and endovascular surgery aim at the removal of the blockage. These therapies are not suitable for the so-called "no option patients" which present multiple artery occlusions with a likelihood of significant limb amputation. Therefore, CLTI represents a significant clinical challenge, and the efforts of developing new treatments have been focused on stimulating angiogenesis in the ischemic muscle. The delivery of pro-angiogenic nucleic acid, protein, and stem cell-based interventions have limited efficacy due to their short survival. Engineered biomaterials have emerged as a promising method to improve the effectiveness of these latter strategies. Several synthetic and natural biomaterials are tested in different formulations aiming to incorporate nucleic acid, proteins, stem cells, macrophages, or endothelial cells in supportive matrices. In this review, an overview of the biomaterials used alone and in combination with growth factors, nucleic acid, and cells in preclinical models is provided and their potential to induce revascularization and regeneration for CLTI applications is discussed.
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Affiliation(s)
- Grazia Marsico
- CÚRAM SFI Research Centre for Medical DevicesNational University of IrelandGalwayIreland
| | - Sergio Martin‐Saldaña
- CÚRAM SFI Research Centre for Medical DevicesNational University of IrelandGalwayIreland
| | - Abhay Pandit
- CÚRAM SFI Research Centre for Medical DevicesNational University of IrelandGalwayIreland
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26
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Ahn YJ, Yun WS, Choi JS, Kim WC, Lee SH, Park DJ, Park JE, Key J, Seo YJ. Biodistribution of poly clustered superparamagnetic iron oxide nanoparticle labeled mesenchymal stem cells in aminoglycoside induced ototoxic mouse model. Biomed Eng Lett 2021; 11:39-53. [PMID: 33747602 DOI: 10.1007/s13534-020-00181-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 12/02/2020] [Accepted: 12/28/2020] [Indexed: 12/12/2022] Open
Abstract
Recently, application of stem cell therapy in regenerative medicine has become an active field of study. Mesenchymal stem cells (MSCs) are known to have a strong ability for homing. MSCs labeled with superparamagnetic iron oxide nanoparticles (SPIONs) exhibit enhanced homing due to magnetic attraction. We have designed a SPION that has a cluster core of iron oxide-based nanoparticles coated with PLGA-Cy5.5. We optimized the nanoparticles for internalization to enable the transport of PCS nanoparticles through endocytosis into MSCs. The migration of magnetized MSCs with SPION by static magnets was seen in vitro. The auditory hair cells do not regenerate once damaged, ototoxic mouse model was generated by administration of kanamycin and furosemide. SPION labeled MSC's were administered through different injection routes in the ototoxic animal model. As result, the intratympanic administration group with magnet had the highest number of cells in the brain followed by the liver, cochlea, and kidney as compared to those in the control groups. The synthesized PCS (poly clustered superparamagnetic iron oxide) nanoparticles, together with MSCs, by magnetic attraction, could synergistically enhance stem cell delivery. The poly clustered superparamagnetic iron oxide nanoparticle labeled in the mesenchymal stem cells have increased the efficacy of homing of the MSC's to the target area by synergetic effect of magnetic attraction and chemotaxis (SDF-1/CXCR4 axis). This technique allows delivery of the stem cells to the areas with limited vasculatures. The nanoparticle in the biomedicine allows drug delivery, thus, the combination of nanomedicince together with the regenerative medicine will provide highly effective therapy.
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Affiliation(s)
- Ye Ji Ahn
- Research Institute of Hearing Enhancement, Yonsei University Wonju College of Medicine, Wonju, 26426 South Korea.,Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do 26426 South Korea
| | - Wan Su Yun
- Department of Biomedical Engineering, Yonsei University, 1 Yonseidae-gil, Wonju, Gangwon- do 26493 South Korea
| | - Jin Sil Choi
- Research Institute of Hearing Enhancement, Yonsei University Wonju College of Medicine, Wonju, 26426 South Korea.,Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do 26426 South Korea
| | - Woo Cheol Kim
- Department of Biomedical Engineering, Yonsei University, 1 Yonseidae-gil, Wonju, Gangwon- do 26493 South Korea
| | - Su Hoon Lee
- Research Institute of Hearing Enhancement, Yonsei University Wonju College of Medicine, Wonju, 26426 South Korea.,Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do 26426 South Korea
| | - Dong Jun Park
- Research Institute of Hearing Enhancement, Yonsei University Wonju College of Medicine, Wonju, 26426 South Korea.,Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do 26426 South Korea
| | - Jeong Eun Park
- Research Institute of Hearing Enhancement, Yonsei University Wonju College of Medicine, Wonju, 26426 South Korea.,Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do 26426 South Korea
| | - Jaehong Key
- Department of Biomedical Engineering, Yonsei University, 1 Yonseidae-gil, Wonju, Gangwon- do 26493 South Korea
| | - Young Joon Seo
- Research Institute of Hearing Enhancement, Yonsei University Wonju College of Medicine, Wonju, 26426 South Korea.,Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do 26426 South Korea
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27
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Cruz-Samperio R, Jordan M, Perriman A. Cell augmentation strategies for cardiac stem cell therapies. Stem Cells Transl Med 2021; 10:855-866. [PMID: 33660953 PMCID: PMC8133336 DOI: 10.1002/sctm.20-0489] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Myocardial infarction (MI) has been the primary cause of death in developed countries, resulting in a major psychological and financial burden for society. Current treatments for acute MI are directed toward rapid restoration of perfusion to limit damage to the myocardium, rather than promoting tissue regeneration and subsequent contractile function recovery. Regenerative cell therapies (CTs), in particular those using multipotent stem cells (SCs), are in the spotlight for treatment post‐MI. Unfortunately, the efficacy of CTs is somewhat limited by their poor long‐term viability, homing, and engraftment to the myocardium. In response, a range of novel SC‐based technologies are in development to provide additional cellular modalities, bringing CTs a step closer to the clinic. In this review, the current landscape of emerging CTs and their augmentation strategies for the treatment post‐MI are discussed. In doing so, we highlight recent advances in cell membrane reengineering via genetic modifications, recombinant protein immobilization, and the utilization of soft biomimetic scaffold interfaces.
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Affiliation(s)
| | - Millie Jordan
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Adam Perriman
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
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28
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Crosby CO, Hillsley A, Kumar S, Stern B, Parekh SH, Rosales A, Zoldan J. Phototunable interpenetrating polymer network hydrogels to stimulate the vasculogenesis of stem cell-derived endothelial progenitors. Acta Biomater 2021; 122:133-144. [PMID: 33359297 PMCID: PMC7983093 DOI: 10.1016/j.actbio.2020.12.041] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 02/08/2023]
Abstract
Vascularization of engineered scaffolds remains a critical obstacle hindering the translation of tissue engineering from the bench to the clinic. We previously demonstrated the robust micro-vascularization of collagen hydrogels with induced pluripotent stem cell (iPSC)-derived endothelial progenitors; however, physically cross-linked collagen hydrogels compact rapidly and exhibit limited strength. We have synthesized an interpenetrating polymer network (IPN) hydrogel comprised of collagen and norbornene-modified hyaluronic acid (NorHA) to address these challenges. This dual-network hydrogel combines the natural cues presented by collagen's binding sites and extracellular matrix (ECM)-mimicking fibrous architecture with the in situ modularity and chemical cross-linking of NorHA. We modulated the IPN hydrogel's stiffness and degradability by varying the concentration and sequence, respectively, of the NorHA peptide cross-linker. Rheological characterization of the photo-mediated gelation process revealed that the IPN hydrogel's stiffness increased with cross-linker concentration and was decoupled from the bulk NorHA content. Conversely, the swelling of the IPN hydrogel decreased linearly with increasing cross-linker concentration. Collagen microarchitecture remained relatively unchanged across cross-linking conditions, although the addition of NorHA delayed collagen fibrillogenesis. Upon iPSC-derived endothelial progenitor encapsulation, robust, lumenized microvascular networks developed in IPN hydrogels over two weeks. Subsequent computational analysis showed that an initial rise in stiffness increased the number of branch points and vessels, but vascular growth was suppressed in high stiffness IPN hydrogels. These results suggest that an IPN hydrogel consisting of collagen and NorHA is highly tunable, compaction resistant, and capable of supporting vasculogenesis.
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Affiliation(s)
- Cody O Crosby
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street, Austin, TX 78712, United States; Department of Physics, Southwestern University, Georgetown, TX, 78626, United States
| | - Alex Hillsley
- Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, 78712, United States
| | - Sachin Kumar
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street, Austin, TX 78712, United States
| | - Brett Stern
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street, Austin, TX 78712, United States
| | - Sapun H Parekh
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street, Austin, TX 78712, United States
| | - Adrianne Rosales
- Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, 78712, United States
| | - Janet Zoldan
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street, Austin, TX 78712, United States.
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29
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Zhang X, Tang H, Mao S, Li B, Zhou Y, Yue H, Wang D, Wang Y, Fu J. Transplanted hair follicle stem cells migrate to the penumbra and express neural markers in a rat model of cerebral ischaemia/reperfusion. Stem Cell Res Ther 2020; 11:413. [PMID: 32967732 PMCID: PMC7510278 DOI: 10.1186/s13287-020-01927-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/16/2020] [Accepted: 09/07/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Ischaemic stroke has become the main cause of death and severe neurological disorders, for which effective restorative treatments are currently limited. While stem cell transplantation offers therapeutic potential through neural regeneration, this approach is associated with the challenges of limited applicable sources. Hair follicle stem cells (HFSCs) are multipotential cells that can differentiate into ectodermal and mesodermal lineages and proliferate for long periods. The therapeutic potentials of HFSCs have not been investigated in ischaemic stroke models, and therefore, in this study, we aimed to determine whether they could survive and migrate to ischaemic areas after a stroke attack. METHODS A rat model of middle cerebral artery ischaemia/reperfusion was established and intravenously administered HFSCs. The potential of HFSCs to migrate and differentiate into neuron-like cells as well as their ability to reduce the infarct size was evaluated. Rat brain tissue samples were collected 2 weeks after cell transplantation and analysed via TTC staining, immunofluorescence and immunohistochemistry methods. The data were statistically analysed and presented as the means ± standard deviations. RESULTS Intravenously administrated rat HFSCs were able to migrate to the penumbra where they expressed neuron-specific markers, reduced the infarct volume and promoted neurological recovery. CONCLUSION HFSC transplantation has therapeutic potential for ischaemic stroke and is, therefore, worthy of further investigation toward possible clinical development for treating stroke patients.
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Affiliation(s)
- Xuemei Zhang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
| | - Hao Tang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
| | - Senlin Mao
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
| | - Bing Li
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
| | - Yinglian Zhou
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
| | - Hui Yue
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
| | - Duo Wang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
| | - Yifei Wang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
| | - Jin Fu
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China.
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30
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Jiang HH, Ji LX, Li HY, Song QX, Bano Y, Chen L, Liu G, Wang M. Combined Treatment With CCR1-Overexpressing Mesenchymal Stem Cells and CCL7 Enhances Engraftment and Promotes the Recovery of Simulated Birth Injury-Induced Stress Urinary Incontinence in Rats. Front Surg 2020; 7:40. [PMID: 32850943 PMCID: PMC7412717 DOI: 10.3389/fsurg.2020.00040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 05/28/2020] [Indexed: 01/07/2023] Open
Abstract
Objective: To observe whether urethral injection of chemokine (c-c motif) ligand 7 (CCL7) and overexpressing CC receptor 1 (CCR1) in mesenchymal stem cells (MSCs) can promote their homing and engraftment to the injured tissue, and improve the recovery of simulated birth injury-induced stress urinary incontinence (SUI) in rats. Methods: Female rats underwent a dual injury consisting of vaginal distension (VD) and pudendal nerve crush (PNC) to induce SUI. Bone marrow-derived MSCs were transduced with lentivirus carrying CCR1 (MSC-CCR1) and green fluorescent protein (GFP). Forty virgin Sprague–Dawley rats were evenly distributed into four groups: sham SUI + MSC-CCR1+CCL7, SUI + MSCs, SUI + MSC-CCR1, and SUI + MSC-CCR1+CCL7 group. The engrafted MSCs in urethra were quantified. Another three groups of rats, including sham SUI + sham MSC-CCR1+CCL7 treatment, SUI + sham MSC-CCR1+CCL7 treatment, and SUI + MSC-CCR1+CCL7 treatment group, were used to evaluate the functional recovery by testing external urethral sphincter electromyography (EUS EMG), pudendal nerve motor branch potentials (PNMBP), and leak point pressure (LPP) 1 week after injury and injection. Urethra and vagina were harvested for histological examination. Results: The SUI + MSC-CCR1+CCL7 group received intravenous injection of CCR1-overexpressing MSCs and local injection of CCL7 after simulated birth injury had the most engraftment of MSCs to the injured tissues and best functional recovery from SUI compared to other groups. Histological examination showed a partial repair in the SUI + MSC-CCR1+CCL7 group. Conclusions: Our study demonstrated combined treatment with CCR1-overexpressing MSCs and CCL7 can increase engraftment of MSCs and promote the functional recovery of simulated birth trauma-induced SUI in rats, which could be a new therapeutic strategy for SUI.
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Affiliation(s)
- Hai-Hong Jiang
- Department of Urology and Andrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ling-Xiao Ji
- Department of Urology and Andrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hai-Yan Li
- Department of Urology and Andrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qi-Xiang Song
- Department of Urology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Yasmeen Bano
- Department of Urology and Andrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lei Chen
- Department of Urology and Andrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guiming Liu
- Department of Surgery/Urology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, United States
| | - Meihao Wang
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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31
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Vascular Remodeling in Moyamoya Angiopathy: From Peripheral Blood Mononuclear Cells to Endothelial Cells. Int J Mol Sci 2020; 21:ijms21165763. [PMID: 32796702 PMCID: PMC7460840 DOI: 10.3390/ijms21165763] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/30/2020] [Accepted: 08/06/2020] [Indexed: 12/13/2022] Open
Abstract
The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45dimCD34+CD133+ mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; p = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.
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Kavanagh DPJ, Lokman AB, Neag G, Colley A, Kalia N. Imaging the injured beating heart intravitally and the vasculoprotection afforded by haematopoietic stem cells. Cardiovasc Res 2020; 115:1918-1932. [PMID: 31062860 PMCID: PMC6803816 DOI: 10.1093/cvr/cvz118] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 03/20/2019] [Accepted: 05/01/2019] [Indexed: 12/16/2022] Open
Abstract
Aims Adequate microcirculatory perfusion, and not just opening of occluded arteries, is critical to salvage heart tissue following myocardial infarction. However, the degree of microvascular perfusion taking place is not known, limited primarily by an inability to directly image coronary microcirculation in a beating heart in vivo. Haematopoietic stem/progenitor cells (HSPCs) offer a potential therapy but little is known about their homing dynamics at a cellular level and whether they protect coronary microvessels. This study used intravital microscopy to image the anaesthetized mouse beating heart microcirculation following stabilization. Methods and results A 3D-printed stabilizer was attached to the ischaemia–reperfusion injured (IRI) beating heart. The kinetics of neutrophil, platelet and HSPC recruitment, as well as functional capillary density (FCD), was imaged post-reperfusion. Laser speckle contrast imaging (LSCI) was used for the first time to monitor ventricular blood flow in beating hearts. Sustained hyperaemic responses were measured throughout reperfusion, initially indicating adequate flow resumption. Intravital microscopy confirmed large vessel perfusion but demonstrated poor transmission of flow to downstream coronary microvessels. Significant neutrophil adhesion and microthrombus formation occurred within capillaries with the latter occluding them, resulting in patchy perfusion and reduced FCD. Interestingly, ‘patrolling’ neutrophils were also observed in capillaries. Haematopoietic stem/progenitor cells readily trafficked through the heart but local retention was poor. Despite this, remarkable anti-thromboinflammatory effects were observed, consequently improving microvascular perfusion. Conclusion We present a novel approach for imaging multiple microcirculatory perturbations in the beating heart with LSCI assessment of blood flow. Despite deceptive hyperaemic responses, increased microcirculatory flow heterogeneity was seen, with non-perfused areas interspersed with perfused areas. Microthrombi, rather than neutrophils, appeared to be the major causative factor. We further applied this technique to demonstrate local stem cell presence is not a pre-requisite to confer vasculoprotection. This is the first detailed in vivo characterization of coronary microcirculatory responses post-reperfusion injury.
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Affiliation(s)
- Dean P J Kavanagh
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Adam B Lokman
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Georgiana Neag
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Abigail Colley
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Neena Kalia
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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Luo F, Jiang W, Xu Y, Liu XM, Wang W, Zhang W, Luo C. The Mechanisms Involved in Mesenchymal Stem Cell Alleviation of Sepsis-Induced Acute Lung Injury in Mice: A Pilot Study. Curr Ther Res Clin Exp 2020; 93:100593. [PMID: 32760471 PMCID: PMC7393454 DOI: 10.1016/j.curtheres.2020.100593] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 06/21/2020] [Indexed: 12/19/2022] Open
Abstract
Background Acute lung injury is a common complication of sepsis in intensive care unit patients. Inflammation is among the main mechanisms of sepsis. Therefore, suppression of inflammation is an important mechanism for sepsis treatment. Mesenchymal stem cells (MSCs) have been reported to exhibit antimicrobial properties. Objective The present study investigated the effects of MSCs on sepsis-induced acute lung injury. Methods Male C57BL/6 mice underwent a cecal ligation and puncture (CLP) operation to induce sepsis and then received either normal saline or MSCs (1 × 106 cells intravenously) at 3 hours after surgery. Survival after surgery was assessed. Lung injury was assessed by histology score, the presence of lung edema, vascular permeability, inflammatory cell infiltration, and cytokine levels in bronchoalveolar lavage fluid. Finally, we tested nuclear factor kappa-light-chain-enhancer of activated B cells activation in lung tissue. Results As expected, CLP caused lung injury as indicated by significant increases in the histopathology score, lung wet to dry weight ratio, and total protein concentration. However, mice treated with MSCs had amelioration of the lung histopathologic changes, lung wet to dry weight ratio, and total protein concentration. The levels of cytokines tumor necrosis factor alpha, interleukin 6, interleukin 1β, and interleukin 17 in bronchoalveolar lavage fluid were dramatically decreased after MSCs treatment. In contrast, expression of interleukin 10 was increased after MSCs treatment. Moreover, mice treated with MSCs had a higher survival rate than the CLP group. Neutrophil infiltration into bronchoalveolar lavage fluid was attenuated after MSCs injection, but the amounts of macrophages observed in the MSC group showed no significant differences compared with the CLP group. In addition, MSCs treatment significantly reduced nuclear factor kappa-light-chain-enhancer of activated B cells activation in lung tissue. Conclusions Based on the above findings, treatment with MSCs dampened the inflammatory response and inhibited nuclear factor kappa-light-chain-enhancer of activated B cells activation in the mouse CLP model. Thus, MSCs may be a potential new agent for the treatment of sepsis-induced acute lung injury. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).
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Affiliation(s)
- Feng Luo
- The Affiliated Hospital of Qingdao University, Shandong, China
| | - Wei Jiang
- The Affiliated Hospital of Qingdao University, Shandong, China
| | - Yan Xu
- The Affiliated Hospital of Qingdao University, Shandong, China
| | - Xue-Mei Liu
- The Affiliated Hospital of Qingdao University, Shandong, China
| | - Wei Wang
- The Affiliated Hospital of Qingdao University, Shandong, China
| | - Wei Zhang
- The Affiliated Hospital of Qingdao University, Shandong, China
| | - Congjuan Luo
- The Affiliated Hospital of Qingdao University, Shandong, China
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Abdolmaleki A, Ghayour MB, Behnam-Rassouli M. Protective effects of acetyl-L-carnitine against serum and glucose deprivation-induced apoptosis in rat adipose-derived mesenchymal stem cells. Cell Tissue Bank 2020; 21:655-666. [PMID: 32564258 DOI: 10.1007/s10561-020-09844-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 06/16/2020] [Indexed: 02/02/2023]
Abstract
Low survival rate of grafted mesenchymal stem cells (MSC) in injured tissue is one of the major limitations of stem cell therapy. One of the most important factors that limits the MSCs survival rate and retention is ischemic stress, which can lead to damage to all components of the cell. In particular, it can damage mitochondria, that play an important role in apoptosis with releasing apoptotic factors. Therefore, we investigated the protective effects of Acetyl-L-carnitine (ALCAR) against serum and glucose deprivation (SGD) in adipose-derived mesenchymal stem cells (AD-MSCs). We measured cell viability, proliferation, and apoptosis in cells experiencing SGD stress for 8 h with exposure to varying concentrations of ALCAR. Results showed that ALCAR protects cells against SGD stress by reducing apoptosis. Its protective effects are associated with reductions in cleaved caspase-3 and attenuation of apoptosis. Result showed that ALCAR exhibits protective effects against SGD-induced damage to AD-MSCs by enhancing the expression of survival signals and by decreasing the expression of death signals.
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Affiliation(s)
- Arash Abdolmaleki
- Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran.,Bio Science and Biotechnology Research Center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran
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Kong Z, Wang Y, Zhang Y, Shan W, Wu J, Wang Q. MicroRNA-126 promotes endothelial progenitor cell proliferation and migration ability via the Notch pathway. Cardiovasc Diagn Ther 2020; 10:490-499. [PMID: 32695628 DOI: 10.21037/cdt-20-178] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Effective regulation of the biological function of endothelial progenitor cells (EPCs) is of great importance in its clinical application. This study aimed to explore the effect of microRNA-126 (miR-126) on the proliferation and migration of EPCs and the possible mechanism involved. Methods EPCs was isolated and cultured in vitro, and differences in the expression of miR-126 in endothelial cells (ECs) and EPCs, respectively, were detected by quantitative real-time PCR (RT-PCR). EPCs proliferation was then observed through CCK8 and colony formation experiments. Flow cytometry was also used to observe changes in the cycle and apoptosis of EPCs, and their migration ability was detected by scratch healing and Transwell assays. RT-PCR and Western blotting were carried out to observe the expression of key mRNA molecules and proteins of the Notch pathway. Results The relative expression of miR-126 in the EPCs group were 1.91±0.21, which was significantly higher than that in the EC group (1.25±0.06, P<0.05). When si-miR-126 and si-NC were transfected into the EPCs, it was found that the proliferation ability of cells in the si-miR-126 group decreased significantly (P<0.05), the apoptotic rate of the cells transfected with si-miR-126 was significantly increased, and the cell cycle was blocked at G0/G1 phase. RT-PCR and Western blotting demonstrated that the mRNA and protein expressions of Notch 1 and HES were significantly decreased in the si-miR-126 group. Conclusions miR-126 can effectively promote the proliferation, invasion, and migration of EPCS, while inhibiting apoptosis, through the Notch1 pathway.
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Affiliation(s)
- Zhaohong Kong
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yunfeng Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yudi Zhang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Wei Shan
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.,Beijing Institute for Brain Disorders, Beijing, China
| | - Jianping Wu
- China National Clinical Research Center for Neurological Diseases, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Qun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China.,Beijing Institute for Brain Disorders, Beijing, China
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Lu XX, Zhao SZ. Gene-based Therapeutic Tools in the Treatment of Cornea Disease. Curr Gene Ther 2020; 19:7-19. [PMID: 30543166 DOI: 10.2174/1566523219666181213120634] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 11/23/2018] [Accepted: 12/11/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND As one of the main blinding ocular diseases, corneal blindness resulted from neovascularization that disrupts the angiogenic privilege of corneal avascularity. Following neovascularization, inflammatory cells are infiltrating into cornea to strengthen corneal injury. How to maintain corneal angiogenic privilege to treat corneal disease has been investigated for decades. METHODOLOGY Local administration of viral and non-viral-mediated anti-angiogenic factors reduces angiogenic protein expression in situ with limited or free of off-target effects upon gene delivery. Recently, Mesenchymal Stem Cells (MSCs) have been studied to treat corneal diseases. Once MSCs are manipulated to express certain genes of interest, they could achieve superior therapeutic efficacy after transplantation. DISCUSSION In the text, we first introduce the pathological development of corneal disease in the aspects of neovascularization and inflammation. We summarize how MSCs become an ideal candidate in cell therapy for treating injured cornea, focusing on cell biology, property and features. We provide an updated review of gene-based therapies in animals and preclinical studies in the aspects of controlling target gene expression, safety and efficacy. Gene transfer vectors are potent to induce candidate protein expression. Delivered by vectors, MSCs are equipped with certain characters by expressing a protein of interest, which facilitates better for MSC-mediated therapeutic intervention for the treatment of corneal disease. CONCLUSION As the core of this review, we discuss how MSCs could be engineered to be vector system to achieve enhanced therapeutic efficiency after injection.
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Affiliation(s)
- Xiao-Xiao Lu
- Tianjin Medical University Eye Hospital and Institute, Tianjin 300384, China
| | - Shao-Zhen Zhao
- Tianjin Medical University Eye Hospital and Institute, Tianjin 300384, China
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Santoso MR, Ikeda G, Tada Y, Jung JH, Vaskova E, Sierra RG, Gati C, Goldstone AB, von Bornstaedt D, Shukla P, Wu JC, Wakatsuki S, Woo YJ, Yang PC. Exosomes From Induced Pluripotent Stem Cell-Derived Cardiomyocytes Promote Autophagy for Myocardial Repair. J Am Heart Assoc 2020; 9:e014345. [PMID: 32131688 PMCID: PMC7335524 DOI: 10.1161/jaha.119.014345] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Induced pluripotent stem cells and their differentiated cardiomyocytes (iCMs) have tremendous potential as patient‐specific therapy for ischemic cardiomyopathy following myocardial infarctions, but difficulties in viable transplantation limit clinical translation. Exosomes secreted from iCMs (iCM‐Ex) can be robustly collected in vitro and injected in lieu of live iCMs as a cell‐free therapy for myocardial infarction. Methods and Results iCM‐Ex were precipitated from iCM supernatant and characterized by protein marker expression, nanoparticle tracking analysis, and functionalized nanogold transmission electron microscopy. iCM‐Ex were then used in in vitro and in vivo models of ischemic injuries. Cardiac function in vivo was evaluated by left ventricular ejection fraction and myocardial viability measurements by magnetic resonance imaging. Cardioprotective mechanisms were studied by JC‐1 (tetraethylbenzimidazolylcarbocyanine iodide) assay, immunohistochemistry, quantitative real‐time polymerase chain reaction, transmission electron microscopy, and immunoblotting. iCM‐Ex measured ≈140 nm and expressed CD63 and CD9. iCM and iCM‐Ex microRNA profiles had significant overlap, indicating that exosomal content was reflective of the parent cell. Mice treated with iCM‐Ex demonstrated significant cardiac improvement post–myocardial infarction, with significantly reduced apoptosis and fibrosis. In vitro iCM apoptosis was significantly reduced by hypoxia and exosome biogenesis inhibition and restored by treatment with iCM‐Ex or rapamycin. Autophagosome production and autophagy flux was upregulated in iCM‐Ex groups in vivo and in vitro. Conclusions iCM‐Ex improve post–myocardial infarction cardiac function by regulating autophagy in hypoxic cardiomyoytes, enabling a cell‐free, patient‐specific therapy for ischemic cardiomyopathy.
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Affiliation(s)
- Michelle R Santoso
- Stanford Cardiovascular Institute Stanford University School of Medicine Stanford CA
| | - Gentaro Ikeda
- Stanford Cardiovascular Institute Stanford University School of Medicine Stanford CA
| | - Yuko Tada
- Stanford Cardiovascular Institute Stanford University School of Medicine Stanford CA
| | - Ji-Hye Jung
- Stanford Cardiovascular Institute Stanford University School of Medicine Stanford CA
| | - Evgeniya Vaskova
- Stanford Cardiovascular Institute Stanford University School of Medicine Stanford CA
| | - Raymond G Sierra
- Hard X-ray Department LCLS SLAC National Accelerator Laboratory Menlo Park CA.,Stanford PULSE Institute SLAC National Accelerator Laboratory Menlo Park CA
| | - Cornelius Gati
- Department of Structural Biology Stanford University School of Medicine Stanford CA
| | - Andrew B Goldstone
- Department of Cardiothoracic Surgery Falk Building Stanford University Medical Center Stanford CA
| | | | - Praveen Shukla
- Stanford Cardiovascular Institute Stanford University School of Medicine Stanford CA
| | - Joseph C Wu
- Stanford Cardiovascular Institute Stanford University School of Medicine Stanford CA
| | - Soichi Wakatsuki
- Department of Structural Biology Stanford University School of Medicine Stanford CA
| | - Y Joseph Woo
- Department of Cardiothoracic Surgery Falk Building Stanford University Medical Center Stanford CA
| | - Phillip C Yang
- Stanford Cardiovascular Institute Stanford University School of Medicine Stanford CA
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Dana D, Pathak SK. A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L. Molecules 2020; 25:E698. [PMID: 32041276 PMCID: PMC7038230 DOI: 10.3390/molecules25030698] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/29/2020] [Accepted: 02/04/2020] [Indexed: 01/06/2023] Open
Abstract
Human cathepsin L belongs to the cathepsin family of proteolytic enzymes with primarily an endopeptidase activity. Although its primary functions were originally thought to be only of a housekeeping enzyme that degraded intracellular and endocytosed proteins in lysosome, numerous recent studies suggest that it plays many critical and specific roles in diverse cellular settings. Not surprisingly, the dysregulated function of cathepsin L has manifested itself in several human diseases, making it an attractive target for drug development. Unfortunately, several redundant and isoform-specific functions have recently emerged, adding complexities to the drug discovery process. To address this, a series of chemical biology tools have been developed that helped define cathepsin L biology with exquisite precision in specific cellular contexts. This review elaborates on the recently developed small molecule inhibitors and probes of human cathepsin L, outlining their mechanisms of action, and describing their potential utilities in dissecting unknown function.
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Affiliation(s)
- Dibyendu Dana
- Chemistry and Biochemistry Department, Queens College of The City University of New York, 65-30 Kissena Blvd, Flushing, NY 11367, USA
- Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York (CUNY), 365 5th Ave, New York, NY 10016, USA
| | - Sanjai K. Pathak
- Chemistry and Biochemistry Department, Queens College of The City University of New York, 65-30 Kissena Blvd, Flushing, NY 11367, USA
- Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York (CUNY), 365 5th Ave, New York, NY 10016, USA
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Interleukin-1 β Enhances Umbilical Cord Mesenchymal Stem Cell Adhesion Ability on Human Umbilical Vein Endothelial Cells via LFA-1/ICAM-1 Interaction. Stem Cells Int 2019; 2019:7267142. [PMID: 31949440 PMCID: PMC6948307 DOI: 10.1155/2019/7267142] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 11/13/2019] [Accepted: 11/19/2019] [Indexed: 12/13/2022] Open
Abstract
The migration of administered mesenchymal stem cells (MSCs) to sites of injury via the bloodstream has been demonstrated. However, the underlying mechanisms of umbilical cord MSC adhesion to endothelial cells during transendothelial migration are still unclear. In this study, our data showed that IL-1β induced LFA-1 expression on MSCs and ICAM-1 expression on HUVECs. We then pretreated MSCs with protein synthesis inhibitor cycloheximide. The results showed that IL-1β induced LFA-1 expression on the surface of MSCs via the protein synthesis pathway. Through the p38 MAPK signaling pathway inhibitor SB 203580, we found that IL-1β induces the expression of LFA-1 through p38 MAPK signaling and enhances ICAM-1 expression in HUVECs. In addition, IL-1β-induced MSC adhesion to HUVECs was found to be inhibited by IL-1RA and the LFA-1 inhibitor lovastatin. These results indicate that IL-1β promotes the cell adhesion of MSCs to HUVECs through LFA-1/ICAM-1 interaction. We address the evidence that the cell adhesion mechanism of IL-1β promotes MSC adhesion to HUVECs. The implications of these findings could enhance the therapeutic potential of MSCs.
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Shen Z, Chen Q, Ying H, Ma Z, Bi X, Li X, Wang M, Jin C, Lai D, Zhao Y, Fu G. Identification of differentially expressed genes in the endothelial precursor cells of patients with type 2 diabetes mellitus by bioinformatics analysis. Exp Ther Med 2019; 19:499-510. [PMID: 31897097 PMCID: PMC6923743 DOI: 10.3892/etm.2019.8239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 10/18/2019] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes mellitus (DM) is a metabolic disease with worldwide prevalence that is associated with a decrease in the number and function of endothelial progenitor cells (EPCs). The aim of the present study was to explore the potential hub genes of EPCs in patients with type 2 DM. Differentially expressed genes (DEGs) were screened from a public microarray dataset (accession no. GSE43950). Pathway and functional enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery. The protein-protein interaction (PPI) network was visualized. The most significantly clustered modules and hub genes were identified using Cytoscape. Furthermore, hub genes were validated by quantitative PCR analysis of EPCs isolated from diabetic and normal subjects. Subsequently, weighted gene co-expression network analysis (WGCNA) was performed to identify the modules incorporating the genes exhibiting the most significant variance. A total of 970 DEGs were obtained and they were mainly accumulated in inflammation-associated pathways. A total of 9 hub genes were extracted from the PPI network and the highest differential expression was determined for the interleukin 8 (IL8) and CXC chemokine ligand 1 (CXCL1) genes. In the WGCNA performed to determine the modules associated with type 2 DM, one module incorporated IL8 and CXCL1. Finally, pathway enrichment of 10% genes in the pink module ordered by intramodular connectivity (IC) was associated with the IL17 and the chemokine signaling pathways. The present results revealed that the expression of IL8 and CXCL1 may serve important roles in the pathophysiology of EPCs during type 2 DM and inflammatory response may be critical for the reduced number and hypofunction of EPCs isolated from patients with diabetes.
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Affiliation(s)
- Zhida Shen
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Qi Chen
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Hangying Ying
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Zetao Ma
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Xukun Bi
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Xiaoting Li
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Meihui Wang
- Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Chongying Jin
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Dongwu Lai
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Yanbo Zhao
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Guosheng Fu
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
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Chen X, Hu JG, Huang YZ, Li S, Li SF, Wang M, Xia HW, Li-Ling J, Xie HQ. Copper promotes the migration of bone marrow mesenchymal stem cells via Rnd3-dependent cytoskeleton remodeling. J Cell Physiol 2019; 235:221-231. [PMID: 31187497 DOI: 10.1002/jcp.28961] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 05/21/2019] [Accepted: 05/22/2019] [Indexed: 02/05/2023]
Abstract
The motility of mesenchymal stem cells (MSCs) is highly related to their homing in vivo, a critical issue in regenerative medicine. Our previous study indicated copper (Cu) might promote the recruitment of endogenous MSCs in canine esophagus defect model. In this study, we investigated the effect of Cu on the motility of bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanism in vitro. Cu supplementation could enhance the motility of BMSCs, and upregulate the expression of hypoxia-inducible factor 1α (Hif1α) at the protein level, and upregulate the expression of rho family GTPase 3 (Rnd3) at messenger RNA and protein level. When Hif1α was silenced by small interfering RNA (siRNA), Cu-induced Rnd3 upregulation was blocked. When Rnd3 was silenced by siRNA, the motility of BMSCs was decreased with or without Cu supplementation, and Cu-induced cytoskeleton remodeling was neutralized. Furthermore, overexpression of Rnd3 also increased the motility of BMSCs and induced cytoskeleton remodeling. Overall, our results demonstrated that Cu enhanced BMSCs migration through, at least in part, cytoskeleton remodeling via Hif1α-dependent upregulation of Rnd3. This study provided an insight into the mechanism of the effect of Cu on the motility of BMSCs, and a theoretical foundation of applying Cu to improve the recruitment of BMSCs in tissue engineering and cytotherapy.
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Affiliation(s)
- Xi Chen
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Jun-Gen Hu
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Yi-Zhou Huang
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Shun Li
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Sheng-Fu Li
- Key Laboratory of Transplant Engineering and Immunology of Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Min Wang
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Hong-Wei Xia
- Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Jesse Li-Ling
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Hui-Qi Xie
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
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Umbilical Cord Mesenchymal Stem Cell Transplantation Prevents Chemotherapy-Induced Ovarian Failure via the NGF/TrkA Pathway in Rats. BIOMED RESEARCH INTERNATIONAL 2019; 2019:6539294. [PMID: 31240219 PMCID: PMC6556346 DOI: 10.1155/2019/6539294] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 03/28/2019] [Accepted: 04/24/2019] [Indexed: 01/07/2023]
Abstract
Chemotherapy leads to a loss of fertility and reproductive endocrine function, thereby increasing the risk of premature ovarian failure (POF). Studies have suggested that the transplantation of mesenchymal stem cells could inhibit apoptosis in ovarian granulosa cells and improve follicular development. In the present study, the effects of human umbilical cord mesenchymal stem cell (UCMSC) transplantation on ovarian function after ovarian damage caused by chemotherapy and the mechanism underlying these effects were investigated. POF model rats were obtained by the intraperitoneal injection of cyclophosphamide, and cultured UCMSCs were transplanted by tail vein injection. Serum estrogen, follicle-stimulating hormone, gonadotropin releasing hormone, and anti-Mullerian hormone levels were detected by ELISA. Folliculogenesis was evaluated by histopathological examination. The expression levels of nerve growth factor (NGF), high affinity nerve growth factor receptor (TrkA), follicle-stimulating hormone receptor (FSHR), and caspase-3 were evaluated by western blotting and RT-qPCR. The natural reproductive capacity was assessed by pregnant rate and numbers of embryos. The results indicated that UCMSC transplantation recovered disturbed hormone secretion and folliculogenesis in POF rats. NGF and TrkA levels increased, while FSHR and caspase-3 decreased. The pregnancy rate of POF rats was improved. Therefore, UCMSCs could reduce ovarian failure due to premature senescence caused by chemotherapy, and the NGF/TrkA signaling pathway was involved in the amelioration of POF.
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Li G, Yu H, Liu N, Zhang P, Tang Y, Hu Y, Zhang Y, Pan C, Deng H, Wang J, Li Q, Tang Z. Overexpression of CX3CR1 in Adipose-Derived Stem Cells Promotes Cell Migration and Functional Recovery After Experimental Intracerebral Hemorrhage. Front Neurosci 2019; 13:462. [PMID: 31133793 PMCID: PMC6517499 DOI: 10.3389/fnins.2019.00462] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 04/24/2019] [Indexed: 12/13/2022] Open
Abstract
Stem cell therapy has emerged as a new promising therapeutic strategy for intracerebral hemorrhage (ICH). However, the efficiency of stem cell therapy is partially limited by low retention and engraftment of the delivered cells. Therefore, it’s necessary to improve the migration ability of stem cells to the injured area in order to save the costs and duration of cell preparation. This study aimed to investigate whether overexpression of CX3CR1, the specific receptor of chemokine fractalkine (FKN), in adipose-derived stem cells (ADSCs) can stimulate the cell migration to the injured area in the brain, improve functional recovery and protect against cell death following experimental ICH. ADSCs were isolated from subcutaneous adipose tissues of rats. ICH was induced by means of an injection of collagenase type VII. ELISA showed that the expression levels of fractalkine/FKN were increased at early time points, with a peak at day 3 after ICH. And it was found that different passages of ADSCs could express the chemokine receptor CX3CR1. Besides, the chemotactic movements of ADSCs toward fractalkine have been verified by transwell migration assay. ADSCs overexpressing CX3CR1 were established through lentivirus transfection. We found that after overexpression of CX3CR1 receptor, the migration ability of ADSCs was increased both in vitro and in vivo. In addition, reduced cell death and improved sensory and motor functions were seen in the mice ICH model. Thus, ADSCs overexpression CX3CR1 might be taken as a promising therapeutic strategy for the treatment of ICH.
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Affiliation(s)
- Gaigai Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haihan Yu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Na Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingxin Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Hu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ye Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chao Pan
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Deng
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiahui Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Li
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhouping Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Crosby CO, Valliappan D, Shu D, Kumar S, Tu C, Deng W, Parekh SH, Zoldan J. Quantifying the Vasculogenic Potential of Induced Pluripotent Stem Cell-Derived Endothelial Progenitors in Collagen Hydrogels. Tissue Eng Part A 2019; 25:746-758. [PMID: 30618333 PMCID: PMC6535961 DOI: 10.1089/ten.tea.2018.0274] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 01/01/2019] [Indexed: 11/12/2022] Open
Abstract
IMPACT STATEMENT Our work reinforces the role of extracellular matrix (ECM) density and matrix metalloprotease activity on the formation of microvasculature from induced pluripotent stem cell (iPSC)-derived vascular cells. The cell-matrix interactions discussed in this study underscore the importance of understanding the role of mechanoregulation and matrix degradation on vasculogenesis and can potentially drive the development of ECM-mimicking angiogenic biomaterials. Furthermore, our work has broader implications concerning the response of iPSC-derived cells to the mechanics of engineered microenvironments. An understanding of these interactions will be critical to creating physiologically relevant transplantable tissue replacements.
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Affiliation(s)
- Cody O. Crosby
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas
| | - Deepti Valliappan
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas
| | - David Shu
- Department of Chemical Engineering, The University of Texas at Austin, Austin, Texas
| | - Sachin Kumar
- Department of Molecular Spectroscopy, Max Planck Institute for Polymer Research, Mainz, Germany
| | - Chengyi Tu
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas
| | - Wei Deng
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas
| | - Sapun H. Parekh
- Department of Molecular Spectroscopy, Max Planck Institute for Polymer Research, Mainz, Germany
| | - Janet Zoldan
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas
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Mohammad-Bagher G, Arash A, Morteza BR, Naser MS, Ali M. Synergistic Effects of Acetyl-l-Carnitine and Adipose-Derived Stromal Cells on Improving Regenerative Capacity of Acellular Nerve Allograft in Sciatic Nerve Defect. J Pharmacol Exp Ther 2019; 368:490-502. [PMID: 30591528 DOI: 10.1124/jpet.118.254540] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 12/19/2018] [Indexed: 12/15/2022] Open
Abstract
The combination of decellularized nerve allograft and adipose-derived stromal cells (ASCs) represents a good alternative to nerve autograft for bridging peripheral nerve defects by providing physical guidance and biologic cues. However, the regeneration outcome of acellular nerve allograft (ANA) is often inferior to autograft. Therefore, we hypothesized that acetyl-l-carnitine (ALCAR) treatment and implantation of ASC-embedded ANA would work synergistically to promote nerve regeneration. Seventy rats were randomly allocated into seven experimental groups (n = 10), including the healthy control group, sham surgery group, autograft group, ANA group, ANA + ASCs group, ANA + ALCAR group (50 mg/kg for 2 weeks), and ANA + ASCs + ALCAR (50 mg/kg for 2 weeks) group. All grafts were implanted to bridge long-gap (10-mm) sciatic nerve defects. Functional, electrophysiological, and morphologic analysis was conducted during the experimental period. We found that ALCAR potentiated the survival and retention of transplanted ASCs and upregulated the expression of neurotrophic factor mRNAs in transplanted grafts. Sixteen weeks following implantation in the rat, the ANA supplemented by ASCs was capable of supporting reinnervation across a 10-mm sciatic nerve gap, with results close to that of the autografts in terms of functional, electrophysiological, and histologic assessments. Results demonstrated that ALCAR treatment improved regenerative effects of ANA combined with ASCs on reconstruction of a 10-mm sciatic nerve defect in rat comparable to those of autograft.
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Affiliation(s)
- Ghayour Mohammad-Bagher
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran (G.M.-B., B.-R.M., M.-S.N., M.A.); Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran (A.A.); and Bio Science and Biotechnology Research center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran (A.A.)
| | - Abdolmaleki Arash
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran (G.M.-B., B.-R.M., M.-S.N., M.A.); Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran (A.A.); and Bio Science and Biotechnology Research center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran (A.A.)
| | - Behnam-Rassouli Morteza
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran (G.M.-B., B.-R.M., M.-S.N., M.A.); Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran (A.A.); and Bio Science and Biotechnology Research center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran (A.A.)
| | - Mahdavi-Shahri Naser
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran (G.M.-B., B.-R.M., M.-S.N., M.A.); Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran (A.A.); and Bio Science and Biotechnology Research center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran (A.A.)
| | - Moghimi Ali
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran (G.M.-B., B.-R.M., M.-S.N., M.A.); Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran (A.A.); and Bio Science and Biotechnology Research center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran (A.A.)
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Crosby CO, Zoldan J. Mimicking the physical cues of the ECM in angiogenic biomaterials. Regen Biomater 2019; 6:61-73. [PMID: 30967961 PMCID: PMC6447000 DOI: 10.1093/rb/rbz003] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 12/02/2018] [Accepted: 12/29/2018] [Indexed: 12/12/2022] Open
Abstract
A functional microvascular system is imperative to build and maintain healthy tissue. Impaired microvasculature results in ischemia, thereby limiting the tissue's intrinsic regeneration capacity. Therefore, the ability to regenerate microvascular networks is key to the development of effective cardiovascular therapies. To stimulate the formation of new microvasculature, researchers have focused on fabricating materials that mimic the angiogenic properties of the native extracellular matrix (ECM). Here, we will review biomaterials that seek to imitate the physical cues that are natively provided by the ECM to encourage the formation of microvasculature in engineered constructs and ischemic tissue in the body.
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Affiliation(s)
- Cody O Crosby
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
| | - Janet Zoldan
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
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47
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Manshadi MD, Navid S, Hoshino Y, Daneshi E, Noory P, Abbasi M. The effects of human menstrual blood stem cells-derived granulosa cells on ovarian follicle formation in a rat model of premature ovarian failure. Microsc Res Tech 2018; 82:635-642. [PMID: 30582244 DOI: 10.1002/jemt.23120] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/16/2018] [Accepted: 08/03/2018] [Indexed: 12/22/2022]
Abstract
Many studies have reported that human endometrial mesenchymal stem cells (HuMenSCs) are capable of repairing damaged tissues. The aim of the present study was to investigate the effects of HuMenSCs transplantation as a treatment modality in premature ovarian failure (POF) associated with chemotherapy-induced ovarian damage. HuMenSCs were isolated from menstrual blood samples of five women. After the in vitro culture of HuMenSCs, purity of the cells was assessed by cytometry using CD44, CD90, CD34, and CD45 FITC conjugate antibody. Twenty-four female Wistar rats were randomly divided into four groups: negative control, positive control, sham, and treatment groups. The rat models of POF used in our study were established by injecting busulfan intraperitoneally into the rats during the first estrus cycle. HuMenSCs were transplanted by injection via the tail vein into the POF-induced rats. Four weeks after POF induction, ovaries were collected and the levels of Amh, Fst, and Fshr expression in the granulosa cell (GC) layer, as well as plasma estradiol (E2) and progesterone (P4) levels were evaluated. Moreover, migration and localization of DiI-labeled HuMenSCs were detected, and the labeled cells were found to be localized in GCs layer of immature follicles. In addition to DiI-labelled HuMenSCs tracking, increased levels of expression of Amh and Fshr and Fst, and the high plasma levels of E2 and P4 confirmed that HuMenSC transplantation had a significant effect on follicle formation and ovulation in the treatment group compared with the negative control (POF) group.
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Affiliation(s)
- Marjan D Manshadi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shadan Navid
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Department of Anatomy, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Yumi Hoshino
- Laboratory of Reproductive Endocrinology, Graduate School of Biosphere Science, Hiroshima University, Hiroshima, Japan
| | - Erfan Daneshi
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Parastoo Noory
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Abbasi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Zheng J, Li H, He L, Huang Y, Cai J, Chen L, Zhou C, Fu H, Lu T, Zhang Y, Yao J, Yang Y. Preconditioning of umbilical cord-derived mesenchymal stem cells by rapamycin increases cell migration and ameliorates liver ischaemia/reperfusion injury in mice via the CXCR4/CXCL12 axis. Cell Prolif 2018; 52:e12546. [PMID: 30537044 PMCID: PMC6496237 DOI: 10.1111/cpr.12546] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 08/11/2018] [Accepted: 08/13/2018] [Indexed: 12/18/2022] Open
Abstract
Objectives Transfusion of umbilical cord‐derived mesenchymal stem cells (UC‐MSCs) is a novel strategy for treatment of various liver diseases. However, the therapeutic effect of UC‐MSCs is limited because only a few UC‐MSCs migrate towards the damaged regions. In this study, we observed the effects of autophagy on the migration of UC‐MSCs in vitro and in a model of liver ischaemia/reperfusion (I/R) injury. Materials and Methods We investigated the effects of autophagy on the status of the cell, release of anti‐inflammatory factors and migration of UC‐MSCs in vitro. The therapeutic effects and in vivo migration of rapamycin‐preconditioned UC‐MSCs were observed in a C57/B6 mouse model of liver I/R injury. Results Induction of autophagy by rapamycin enhanced the ability of UC‐MSCs to migrate and release anti‐inflammatory cytokines as well as increased expression of CXCR4 without affecting cell viability. Inhibition of CXCR4 activation markedly decreased migration of these cells. In a mouse model of liver I/R injury, we found significantly upregulated expression of CXCR12 in the damaged liver. More rapamycin‐preconditioned UC‐MSCs migrated towards the ischaemic regions than 3‐methyladenine‐preconditioned or non‐preconditioned UC‐MSCs, leading to improvement in hepatic performance, pathological changes and levels of inflammatory cytokines. These effects were abolished by AMD3100. Conclusions Preconditioning of UC‐MSCs by rapamycin afforded increased protection against liver I/R injury by enhancing immunosuppression and strengthening the homing and migratory capacity of these cells via the CXCR4/CXCL12 axis.
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Affiliation(s)
- Jun Zheng
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hui Li
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liying He
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Yiming Huang
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jianye Cai
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liang Chen
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chaorong Zhou
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hongyuan Fu
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tongyu Lu
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yingcai Zhang
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jia Yao
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yang Yang
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Zhu H, Wang X, Han Y, Zhang W, Xin W, Zheng X, Zhang J. Icariin promotes the migration of bone marrow stromal cells via the SDF-1α/HIF-1α/CXCR4 pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:4023-4031. [PMID: 30538428 PMCID: PMC6254989 DOI: 10.2147/dddt.s179989] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Purpose In this study, a series of in vitro experiments were performed to investigate the molecular mechanisms underlying cell migration promoted by icariin (ICA) at low concentrations. Materials and methods Bone marrow stromal cells (BMSCs) were cultured with different concentrations of ICA to verify whether it can enhance the efficiency of BMSCs migration. Western blot was employed to measure the expression of hypoxia-inducible factor-1α (HIF-1α) and C-X-C chemokine receptor type 4 (CXCR4) at different time points in BMSCs treated with ICA. Subsequently, we evaluated the function of HIF-1α in the expression of CXCR4 and the migration of cells by transfecting plasmid HIF-1α small interfering RNA (siHIF-1α) into BMSCs model. Results Our data indicated that different concentrations of ICA (10, 1, and 0.1 µM) further enhanced the chemotactic capability of SDF-1α, and the most prominent cell migration stimulatory effect was observed with 1 µM ICA. Furthermore, ICA significantly enhanced the protein levels of CXCR4 and HIF-1α, and this effect was blocked by ICI 12,780 (estrogen receptor antagonis). Moreover, transfection of BMSCs with siHIF-1α reduced CXCR4 expression, suggesting that HIF-1α can regulate the migration of cells by influencing the expression of CXCR4. Conclusion ICA promoted BMSCs migration via the activation of HIF-1α and further regulated the expression of CXCR4, suggesting that ICA might have beneficial effects in stem cell therapy.
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Affiliation(s)
- Haiyan Zhu
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, China, .,Department of Orthodontics, School of Stomatology, Shandong University, Jinan, Shandong Province, China, .,Department of Stomatology, Weihai Municipal Hospital, Weihai, Shandong Province, China
| | - Xuxia Wang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, China, .,Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan, Shandong Province, China
| | - Yuanyuan Han
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, China, .,Department of Orthodontics, School of Stomatology, Shandong University, Jinan, Shandong Province, China,
| | - Wenjuan Zhang
- Department of Stomatology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Wei Xin
- Department of Stomatology, Weihai Municipal Hospital, Weihai, Shandong Province, China
| | - Xiaotao Zheng
- Department of Stomatology, Weihai Municipal Hospital, Weihai, Shandong Province, China
| | - Jun Zhang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, Shandong Province, China, .,Department of Orthodontics, School of Stomatology, Shandong University, Jinan, Shandong Province, China,
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50
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Huang S, Ren Y, Wang X, Lazar L, Ma S, Weng G, Zhao J. Application of Ultrasound-Targeted Microbubble Destruction-Mediated Exogenous Gene Transfer in Treating Various Renal Diseases. Hum Gene Ther 2018; 30:127-138. [PMID: 30205715 DOI: 10.1089/hum.2018.070] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Chronic renal disease or acute renal injury could result in end-stage renal disease or renal failure. Sonoporation, induced by ultrasound-targeted microbubble destruction (UTMD), has evolved as a new technology for gene delivery. It increases the transfection efficiency of the genes into target kidney tissues. Moreover, UTMD-mediated gene delivery can directly repair the damaged tissues or improve the recruitment and homing of stem cells in the recovery of injured tissues, which has the potential to act as a non-viral and effective method to current gene therapy. This article reviews the mechanisms and applications of UTMD in terms of renal disease, including diabetic nephropathy, renal carcinoma, acute kidney injury, renal interstitial fibrosis, nephrotoxic nephritis, urinary stones, and acute rejection.
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Affiliation(s)
- Shuaishuai Huang
- 1 Urology and Nephrology Institute of Ningbo University, Ningbo Urology and Nephrology Hospital, Ningbo, P.R. China
| | - Yu Ren
- 1 Urology and Nephrology Institute of Ningbo University, Ningbo Urology and Nephrology Hospital, Ningbo, P.R. China
| | - Xue Wang
- 1 Urology and Nephrology Institute of Ningbo University, Ningbo Urology and Nephrology Hospital, Ningbo, P.R. China
| | - Lissy Lazar
- 2 Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, Medicine School of Ningbo University, Ningbo, P.R. China
| | - Suya Ma
- 1 Urology and Nephrology Institute of Ningbo University, Ningbo Urology and Nephrology Hospital, Ningbo, P.R. China
| | - Guobin Weng
- 1 Urology and Nephrology Institute of Ningbo University, Ningbo Urology and Nephrology Hospital, Ningbo, P.R. China
| | - Jinshun Zhao
- 2 Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, Medicine School of Ningbo University, Ningbo, P.R. China
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