|
1
|
Morimoto K, Nakashima A, Ishiuchi N, Miyasako K, Tanaka Y, Sasaki K, Matsuda G, Maeda S, Miyaki S, Masaki T. Renal protective effects of extracellular vesicle-encapsulated tumor necrosis factor-α-induced protein 6 derived from mesenchymal stem cells. Stem Cells 2025; 43:sxaf022. [PMID: 40249362 DOI: 10.1093/stmcls/sxaf022] [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: 12/04/2024] [Accepted: 04/04/2025] [Indexed: 04/19/2025]
Abstract
Acute kidney injury (AKI) is involved in subsequent chronic kidney disease (CKD) development, and effective treatments to prevent AKI to CKD progression are lacking. Mesenchymal stem cells (MSCs) are emerging as a promising cellular therapy to impede such progression through the secretion of various humoral factors. Among these factors, tumor necrosis factor-α-induced protein 6 (TSG-6) has a central role in the anti-inflammatory effects of MSCs. However, the mechanisms by which MSCs secrete TSG-6 and exert anti-inflammatory effects are not fully clarified. Here, we investigated these mechanisms using TSG-6-overexpressing MSCs (TSG-6 MSCs) with an adeno-associated virus. Extracellular vesicles (EVs) were isolated from MSC culture supernatants by ultracentrifugation. MSCs were injected through the abdominal aorta into rats with ischemia-reperfusion injury (IRI) to evaluate their anti-inflammatory and anti-fibrotic effects. Additionally, we explored natural compounds that increased TSG-6 expression in MSCs. Most TSG-6 was immediately secreted in EVs and was not stored intracellularly. Administration of TSG-6 MSCs strongly suppressed renal fibrosis and inflammation in IRI rats. Although EVs and conditioned medium from TSG-6 MSCs (TSG-6 MSC-CM) strongly promoted polarization of M2 macrophages, TSG-6 MSC-CM after EV depletion promoted it only slightly. Moreover, TSG-6 MSC-CM enhanced regulatory T-cell induction. MSCs treated with indole-3-carbinol had enhanced TSG-6 expression and markedly suppressed IRI-induced renal fibrosis. Taken together, TSG-6 is secreted in EVs from MSCs and exerts potent anti-inflammatory effects by promoting M2 macrophage polarization and regulatory T-cell induction. Administration of MSCs with enhanced TSG-6 secretion is a promising therapeutic strategy to impede AKI to CKD progression.
Collapse
Affiliation(s)
- Keisuke Morimoto
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
| | - Ayumu Nakashima
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
- Department of Nephrology, Graduate School of Medicine, University of Yamanashi, Yamanashi, 409-3898, Japan
| | - Naoki Ishiuchi
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Kisho Miyasako
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
| | - Yoshiki Tanaka
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
| | - Kensuke Sasaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
| | - Go Matsuda
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
- Department of Research and Development, TWOCELLS Company, Limited, Hiroshima, 732-0816, Japan
| | - Satoshi Maeda
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
- Department of Research and Development, TWOCELLS Company, Limited, Hiroshima, 732-0816, Japan
| | - Shigeru Miyaki
- Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
| |
Collapse
|
|
2
|
Pearson JJ, Mao J, Temenoff JS. Effects of Release of TSG-6 from Heparin Hydrogels on Supraspinatus Muscle Regeneration. Tissue Eng Part A 2025; 31:195-207. [PMID: 39556321 DOI: 10.1089/ten.tea.2024.0241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2024] Open
Abstract
Muscle degeneration after rotator cuff tendon tear is a significant clinical problem. In these experiments, we developed a poly(ethylene glycol)-based injectable granular hydrogel containing two heparin derivatives (fully sulfated [Hep] and fully desulfated [Hep-]) as well as a matrix metalloproteinase-sensitive peptide to promote sustained release of tumor necrosis factor-stimulated gene 6 (TSG-6) over 14+ days in vivo in a rat model of rotator cuff muscle injury. The hydrogel formulations demonstrated similar release profiles in vivo, thus facilitating comparisons between delivery from heparin derivatives on the level of tissue repair in two different areas of muscle (near the myotendious junction [MTJ] and in the muscle belly [MB]) that have been shown previously to have differing responses to rotator cuff tendon injury. We hypothesized that sustained delivery of TSG-6 would enhance the anti-inflammatory response following rotator cuff injury through macrophage polarization and that release from Hep would potentiate this effect throughout the muscle. Inflammatory/immune cells, satellite cells, and fibroadipogenic progenitor cells were analyzed by flow cytometry 3 and 7 days after injury and hydrogel injection, while metrics of muscle healing were examined via immunohistochemistry up to day 14. Results showed controlled delivery of TSG-6 from Hep caused heightened macrophage response (day 7 macrophages, 4.00 ± 1.85% single cells, M2a, 3.27 ± 1.95% single cells) and increased markers of early muscle regeneration (embryonic heavy chain staining) by day 7, particularly in the MTJ region of the muscle. This work provides a novel strategy for localized, controlled delivery of TSG-6 to enhance muscle healing after rotator cuff tear.
Collapse
Affiliation(s)
- Joseph J Pearson
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech, Emory University, Atlanta, Georgia, USA
| | - Jiahui Mao
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech, Emory University, Atlanta, Georgia, USA
| | - Johnna S Temenoff
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech, Emory University, Atlanta, Georgia, USA
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
| |
Collapse
|
|
3
|
Gakhar D, Joshi H, Makkar D, Taneja N, Arora A, Rakha A. Machine learning reveals the rules governing the efficacy of mesenchymal stromal cells in septic preclinical models. Stem Cell Res Ther 2024; 15:289. [PMID: 39256841 PMCID: PMC11389403 DOI: 10.1186/s13287-024-03873-3] [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: 12/29/2023] [Accepted: 08/01/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND Mesenchymal Stromal Cells (MSCs) are the preferred candidates for therapeutics as they possess multi-directional differentiation potential, exhibit potent immunomodulatory activity, are anti-inflammatory, and can function like antimicrobials. These capabilities have therefore encouraged scientists to undertake numerous preclinical as well as a few clinical trials to access the translational potential of MSCs in disease therapeutics. In spite of these efforts, the efficacy of MSCs has not been consistent-as is reflected in the large variation in the values of outcome measures like survival rates. Survival rate is a resultant of complex cascading interactions that not only depends upon upstream experimental factors like dosage, time of infusion, type of transplant, etc.; but is also dictated, post-infusion, by intrinsic host specific attributes like inflammatory microniche including proinflammatory cytokines and alarmins released by the damaged host cells. These complex interdependencies make a researcher's task of designing MSC transfusion experiments challenging. METHODS In order to identify the rules and associated attributes that influence the final outcome (survival rates) of MSC transfusion experiments, we decided to apply machine learning techniques on manually curated data collected from available literature. As sepsis is a multi-faceted condition that involves highly dysregulated immune response, inflammatory environment and microbial invasion, sepsis can be an efficient model to verify the therapeutic effects of MSCs. We therefore decided to implement rule-based classification models on data obtained from studies involving interventions of MSCs in sepsis preclinical models. RESULTS The rules from the generated graph models indicated that survival rates, post-MSC-infusion, are influenced by factors like source, dosage, time of infusion, pre-Interleukin-6 (IL-6)/ Tumour Necrosis Factor- alpha (TNF-α levels, etc. CONCLUSION: This approach provides important information for optimization of MSCs based treatment strategies that may help the researchers design their experiments.
Collapse
Affiliation(s)
- Diksha Gakhar
- Department of Translational and Regenerative Medicine, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Himanshu Joshi
- Department of Medical Microbiology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Diksha Makkar
- Department of Translational and Regenerative Medicine, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Neelam Taneja
- Department of Medical Microbiology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Amit Arora
- Department of Medical Microbiology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh, India.
| | - Aruna Rakha
- Department of Translational and Regenerative Medicine, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh, India.
| |
Collapse
|
|
4
|
Pearson JJ, Mao J, Temenoff JS. Effects of Release of TSG-6 from Heparin Hydrogels on Supraspinatus Muscle Regeneration. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.20.608812. [PMID: 39229126 PMCID: PMC11370378 DOI: 10.1101/2024.08.20.608812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Muscle degeneration after rotator cuff tendon tear is a significant clinical problem. In these experiments, we developed a poly(ethylene glycol)-based injectable granular hydrogel containing two heparin derivatives (fully sulfated (Hep) and fully desulfated (Hep-)) as well as a matrix metalloproteinase-sensitive peptide to promote sustained release of Tumor Necrosis Factor Stimulated Gene 6 (TSG-6) over 14+ days in vivo in a rat model of rotator cuff muscle injury. The hydrogel formulations demonstrated similar release profiles in vivo , thus facilitating comparisons between delivery from heparin derivatives on level of tissue repair in two different areas of muscle (near the myotendious junction (MTJ) and in the muscle belly (MB)) that have been shown previously to have differing responses to rotator cuff tendon injury. We hypothesized that sustained delivery of TSG-6 would enhance the anti-inflammatory response following rotator cuff injury through macrophage polarization, and that release from a fully sulfated heparin derivative (Hep) would potentiate this effect throughout the muscle. Inflammatory/immune cells, satellite cells, and fibroadipogenic progenitor cells, were analyzed by flow cytometery 3 and 7 days after injury and hydrogel injection, while metrics of muscle healing were examined via immunohistochemistry up to Day 14. Results showed controlled delivery of TSG-6 from Hep caused heightened macrophage response (Day 14 macrophages, 4.00 ± 1.85% single cells, M2a, 3.27 ± 1.95% single cells) and increased markers of early muscle regeneration (embryonic heavy chain staining) by Day 7, particularly in the MTJ region of the muscle, compared to release from desulfated heparin hydrogels. This work provides a novel strategy for localized, controlled delivery of TSG-6 to enhance muscle healing after rotator cuff tear. IMPACT STATEMENT Rotator cuff tear is a significant problem that can cause muscle degeneration. In this study, a hydrogel particle system was developed for sustained release of an anti-inflammatory protein, Tumor Necrosis Factor Stimulated Gene 6 (TSG-6), to injured muscle. Release of the protein from a fully sulfated heparin hydrogel-based carrier demonstrated greater changes in amount inflammatory cells and more early regenerative effects than a less-sulfated carrier. Thus, this work provides a novel strategy for localized, controlled delivery of an anti-inflammatory protein to enhance muscle healing after rotator cuff tear.
Collapse
|
|
5
|
Hum C, Tahir U, Mei SHJ, Champagne J, Fergusson DA, Lalu M, Stewart DJ, Walley K, Marshall J, dos Santos CC, Winston BW, Mendelson AA, Dave C, McIntyre L. Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cell Therapy in Preclinical Models of Sepsis: A Systematic Review and Meta-analysis. Stem Cells Transl Med 2024; 13:346-361. [PMID: 38381583 PMCID: PMC11016835 DOI: 10.1093/stcltm/szae003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 11/11/2023] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND In preclinical studies, mesenchymal stromal cells (MSCs), including umbilical cord-derived MSCs (UC-MSCs), demonstrate the ability to modulate numerous pathophysiological processes related to sepsis; however, a systematic synthesis of the literature is needed to assess the efficacy of UC-MSCs for treating sepsis. OBJECTIVE To examine the effects of UC-MSCs on overall mortality (primary outcome) as well as on organ dysfunction, coagulopathy, endothelial permeability, pathogen clearance, and systemic inflammation (secondary outcomes) at prespecified time intervals in preclinical models of sepsis. METHODS A systematic search was conducted on Embase, Ovid MEDLINE, and Web of Science up to June 20, 2023. Preclinical controlled studies using in vivo sepsis models with systemic UC-MSC administration were included. Meta-analyses were conducted and expressed as odds ratios (OR) and ratios of the weighted means with 95% CI for categorical and continuous data, respectively. Risk of bias was assessed with the SYRCLE tool. RESULTS Twenty-six studies (34 experiments, n = 1258 animals) were included in this review. Overall mortality was significantly reduced with UC-MSC treatment as compared to controls (OR: 0.26, 95% CI: 0.18-0.36). At various prespecified time intervals, UC-MSCs reduced surrogate measures of organ dysfunction related to the kidney, liver, and lung; reduced coagulopathy and endothelial permeability; and enhanced pathogen clearance from multiple sites. UC-MSCs also modulated systemic inflammatory mediators. No studies were rated as low risk across all SYCLE domains. CONCLUSIONS These results demonstrate the efficacy of UC-MSC treatment in preclinical sepsis models and highlight their potential as a therapeutic intervention for septic shock.
Collapse
Affiliation(s)
- Christine Hum
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Usama Tahir
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Shirley H J Mei
- Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Josee Champagne
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Dean A Fergusson
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Manoj Lalu
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Department of Anesthesiology and Pain Medicine, University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada
| | - Duncan J Stewart
- Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Keith Walley
- Department of Medicine, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada
| | - John Marshall
- Department of Surgery (Critical Care), University of Toronto, Toronto, ON, Canada
| | - Claudia C dos Santos
- Keenan Research Centre for Biomedical Science and Interdepartmental Division of Critical Care, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
| | - Brent W Winston
- Department of Critical Care Medicine, University of Calgary, Calgary, AB, Canada
| | - Asher A Mendelson
- Section of Critical Care Medicine, Department of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Chintan Dave
- Division of Critical Care Medicine, Department of Medicine, Western University, London, ON, Canada
| | - Lauralyn McIntyre
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Medicine (Division of Critical Care), University of Ottawa, Ottawa, ON, Canada
- Department of Medicine (Critical Care), The Ottawa Hospital, Ottawa Hospital Research Institute, Centre for Transfusion and Critical Care Research, Ottawa, ON, Canada
| |
Collapse
|
|
6
|
Norte-Muñoz M, García-Bernal D, García-Ayuso D, Vidal-Sanz M, Agudo-Barriuso M. Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina. Neural Regen Res 2024; 19:542-547. [PMID: 37721282 PMCID: PMC10581591 DOI: 10.4103/1673-5374.380876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/25/2023] [Accepted: 05/11/2023] [Indexed: 09/19/2023] Open
Abstract
Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models. Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration, namely trophic factor deprivation and neuroinflammation. Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement. However, little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system. Here, we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system, focusing on recent work in the retina and the importance of the type of transplantation.
Collapse
Affiliation(s)
- María Norte-Muñoz
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - David García-Bernal
- Grupo de Investigación Trasplante Hematopoyético y Terapia celular, Departamento de Bioquímica e Inmunología. Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - Diego García-Ayuso
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - Manuel Vidal-Sanz
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| | - Marta Agudo-Barriuso
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, 30120 Murcia, Spain
| |
Collapse
|
|
7
|
Luo C, Luo F, Che L, Zhang H, Zhao L, Zhang W, Man X, Bu Q, Luan H, Zhou B, Zhou H, Xu Y. Mesenchymal stem cells protect against sepsis-associated acute kidney injury by inducing Gal-9/Tim-3 to remodel immune homeostasis. Ren Fail 2023; 45:2187229. [PMID: 36883358 PMCID: PMC10013538 DOI: 10.1080/0886022x.2023.2187229] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
OBJECTIVE The present study investigated the specific mechanism by which mesenchymal stem cells (MSCs) protect against sepsis-associated acute kidney injury (SA-AKI). METHODS Male C57BL/6 mice underwent cecal ligation and puncture surgery to induce sepsis and then received either normal IgG or MSCs (1 × 106 cells, intravenously) plus Gal-9 or soluble Tim-3 3 h after surgery. RESULTS After cecal ligation and puncture surgery, the mice injected with Gal-9 or MSCs plus Gal-9 had a higher survival rate than the mice in the IgG treatment group. Treatment with MSCs plus Gal-9 decreased serum creatinine and blood urea nitrogen levels, improved tubular function recovery, reduced IL-17 and RORγt levels and induced IL-10 and FOXP3 expression. Additionally, the Th17/Treg cell balance was altered. However, when soluble Tim-3 was used to block the Gal-9/Tim-3 pathway, the septic mice developed kidney injury and exhibited increased mortality. Treatment with MSCs plus soluble Tim-3 blunted the therapeutic effect of MSCs, inhibited the induction of Tregs, and suppressed the inhibition of differentiation into Th17 cells. CONCLUSION Treatment with MSCs significantly reversed the Th1/Th2 balance. Thus, the Gal-9/Tim-3 pathway may be an important mechanism of MSC-mediated protection against SA-AKI.
Collapse
Affiliation(s)
- Congjuan Luo
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Feng Luo
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Lin Che
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Hui Zhang
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Long Zhao
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Wei Zhang
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Xiaofei Man
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Quandong Bu
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Hong Luan
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Bin Zhou
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Haiyan Zhou
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Yan Xu
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
- CONTACT Yan Xu Department of Nephrology, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao, 266003, Shandong, People's Republic of China
| |
Collapse
|
|
8
|
Pan W, Gu L, Yang H, Xu C, Yang Z, Lu Q, Shi Y, Zhang L, Shao J, Chen Y, Pan X, Wu F, Pan R, Liang J, Zhang L. Repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in cynomolgus monkeys by intravenous and subcutaneous injection. Front Cell Dev Biol 2023; 11:1273723. [PMID: 38020919 PMCID: PMC10630163 DOI: 10.3389/fcell.2023.1273723] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/10/2023] [Indexed: 12/01/2023] Open
Abstract
Human umbilical cord mesenchymal stem cells (hUC-MSCs) are proposed for the treatment of acute lung injury and atopic dermatitis. To advance hUC-MSC entry into clinical trials, the effects of hUC-MSCs on the general toxicity, immune perturbation and toxicokinetic study of hUC-MSCs in cynomolgus monkeys were assessed. hUC-MSCs were administered to cynomolgus monkeys by intravenous infusion of 3.0 × 106 or 3.0 × 107cells/kg or by subcutaneous injection of 3.0 × 107cells/kg twice a week for 3 weeks followed by withdrawal and observation for 6 weeks. Toxicity was assessed by clinical observation, clinical pathology, ophthalmology, immunotoxicology and histopathology. Moreover, toxicokinetic study was performed using a validated qPCR method after the first and last dose. After 3rd or 4th dosing, one or three the monkeys in the intravenous high-dose group exhibited transient coma, which was eliminated by slow-speed infusion after 5th or 6th dosing. In all dose groups, hUC-MSCs significantly increased NEUT levels and decreased LYMPH and CD3+ levels, which are related to the immunosuppressive effect of hUC-MSCs. Subcutaneous nodules and granulomatous foci were found at the site of administration in all monkeys in the subcutaneous injection group. Other than above abnormalities, no obvious systemic toxicity was observed in any group. The hUC-MSCs was detectable in blood only within 1 h after intravenous and subcutaneous administration. The present study declared the preliminary safety of hUC-MSCs, but close monitoring of hUC-MSCs for adverse effects, such as coma induced by intravenous infusion, is warranted in future clinical trials.
Collapse
Affiliation(s)
- Wei Pan
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| | - Liqiang Gu
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| | - Hongzhong Yang
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| | - Cong Xu
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| | - Zhengbiao Yang
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| | - Qijiong Lu
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| | - Yuhua Shi
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| | - Lili Zhang
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| | - Jinjin Shao
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| | - Yunxiang Chen
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| | - Xin Pan
- Zhejiang Key Laboratory of Cell‐Based Drug and Applied Technology Development, S-Evans Biosciences Co, Ltd., Hangzhou, China
| | - Feifei Wu
- Zhejiang Key Laboratory of Cell‐Based Drug and Applied Technology Development, S-Evans Biosciences Co, Ltd., Hangzhou, China
| | - Ruolang Pan
- Zhejiang Key Laboratory of Cell‐Based Drug and Applied Technology Development, S-Evans Biosciences Co, Ltd., Hangzhou, China
| | - Jinfeng Liang
- Zhejiang Center for Drugs and Cosmetics Evaluation, Zhejiang Province Food and Drug Administration, Hangzhou, China
| | - Lijiang Zhang
- Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China
- Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China
| |
Collapse
|
|
9
|
Bhaskar V, Saini S, Ansari S, Ghai S, Thakur A, Chopra S, Verma V, Malakar D. Allogenic adipose derived mesenchymal stem cells are effective than antibiotics in treating endometritis. Sci Rep 2023; 13:11280. [PMID: 37438398 DOI: 10.1038/s41598-023-36820-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 06/10/2023] [Indexed: 07/14/2023] Open
Abstract
Endometritis is a uterine inflammatory disease that causes reduced livestock fertility, milk production and lifespan leading to significant economic losses to the dairy industry. Mesenchymal stem cells (MSC) may act as an alternative for inefficacy of antibiotics and rising antibiotic resistance in endometritis. The present study aimed to cure the chronic endometritic buffaloes using allogenic adipose-derived MSCs (AD-MSC). AD-MSCs were isolated from buffalo adipose tissue and characterized by multilineage differentiation as well as MSC-specific markers. The in vivo safety and efficacy were assessed after infusion of AD-MSCs. In safety trial, cells were administered in healthy buffaloes via different routes (IV and IC) followed by examination of clinical and hematological parameters. In efficacy study, AD-MSCs treatments (IV and IC) and antibiotic therapy (ABT) in endometritic buffaloes were comparatively evaluated. AD-MSCs did not induced any immunological reaction in treated buffaloes. PMN count, CRP levels and VDS were significantly (p ≤ 0.05) reduced after AD-MSCs infusions in IV and IC groups and no significant difference was observed in antibiotic group. The IV group was marked with 50% absolute risk reduction in endometritis and 50% live calf births after artificial insemination in comparison with ABT group. Anti-inflammatory cytokines (IL4 and IL10) and anti-microbial peptides (PI3, CATHL4, LCN2 and CST3) expressions were significantly (p ≤ 0.05) upregulated in IV group. The calf delivery rate after the treatments in IV group was higher (50%, 3 calves) than the other groups (IC: 33.3%, 2 calves; ABT: 16.6%, 1 calf). In conclusion, the administration of AD-MSCs through IV route was found to be safe and efficacious for alleviating chronic endometritis in dairy buffaloes.
Collapse
Affiliation(s)
- Vinay Bhaskar
- Cell and Molecular Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal, India, 132001
| | - Sikander Saini
- Cell and Molecular Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal, India, 132001
| | - Shama Ansari
- Cell and Molecular Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal, India, 132001
| | - Shubham Ghai
- Cell and Molecular Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal, India, 132001
| | - Abhishek Thakur
- Cell and Molecular Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal, India, 132001
| | - Suman Chopra
- Cell and Molecular Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal, India, 132001
| | - Vivekananda Verma
- Cell and Molecular Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal, India, 132001
| | - Dhruba Malakar
- Cell and Molecular Biology Lab, Animal Biotechnology Centre, National Dairy Research Institute, Karnal, India, 132001.
| |
Collapse
|
|
10
|
Blanco NG, Machado NM, Castro LL, Antunes MA, Takiya CM, Trugilho MRO, Silva LR, Paes Leme AF, Domingues RR, Pauletti BA, Miranda BT, Silva JD, Dos Santos CC, Silva PL, Rocco PRM, Cruz FF. Extracellular Vesicles from Different Sources of Mesenchymal Stromal Cells Have Distinct Effects on Lung and Distal Organs in Experimental Sepsis. Int J Mol Sci 2023; 24:ijms24098234. [PMID: 37175936 PMCID: PMC10179270 DOI: 10.3390/ijms24098234] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/24/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
The effects of the administration of mesenchymal stromal cells (MSC) may vary according to the source. We hypothesized that MSC-derived extracellular vesicles (EVs) obtained from bone marrow (BM), adipose (AD), or lung (L) tissues may also lead to different effects in sepsis. We profiled the proteome from EVs as a first step toward understanding their mechanisms of action. Polymicrobial sepsis was induced in C57BL/6 mice by cecal ligation and puncture (SEPSIS) and SHAM (control) animals only underwent laparotomy. Twenty-four hours after surgery, animals in the SEPSIS group were randomized to receive saline or 3 × 106 MSC-derived EVs from BM, AD, or L. The diffuse alveolar damage was decreased with EVs from all three sources. In kidneys, BM-, AD-, and L-EVs reduced edema and expression of interleukin-18. Kidney injury molecule-1 expression decreased only in BM- and L-EVs groups. In the liver, only BM-EVs reduced congestion and cell infiltration. The size and number of EVs from different sources were not different, but the proteome of the EVs differed. BM-EVs were enriched for anti-inflammatory proteins compared with AD-EVs and L-EVs. In conclusion, BM-EVs were associated with less organ damage compared with the other sources of EVs, which may be related to differences detected in their proteome.
Collapse
Affiliation(s)
- Natália G Blanco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Natália M Machado
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Ligia L Castro
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Mariana A Antunes
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Christina M Takiya
- Laboratory of Immunopathology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Monique R O Trugilho
- Toxinology Laboratory, Center for Technological Development Health, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, RJ, Brazil
| | - Luana R Silva
- Toxinology Laboratory, Center for Technological Development Health, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, RJ, Brazil
| | - Adriana F Paes Leme
- Mass Spectrometry Laboratory, Brazilian Bioscience National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials, Campinas 13083-970, SP, Brazil
| | - Romênia R Domingues
- Mass Spectrometry Laboratory, Brazilian Bioscience National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials, Campinas 13083-970, SP, Brazil
| | - Bianca A Pauletti
- Mass Spectrometry Laboratory, Brazilian Bioscience National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials, Campinas 13083-970, SP, Brazil
| | - Beatriz T Miranda
- Laboratory of Cellular and Molecular Cardiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Johnatas D Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Claudia C Dos Santos
- The Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, 209 Victoria Street, Toronto, ON M5B 1T8, Canada
- Institute of Medical Sciences, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
- Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
| | - Pedro L Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Patricia R M Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Fernanda F Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| |
Collapse
|
|
11
|
Lopes-Pacheco M, Rocco PRM. Functional enhancement strategies to potentiate the therapeutic properties of mesenchymal stromal cells for respiratory diseases. Front Pharmacol 2023; 14:1067422. [PMID: 37007034 PMCID: PMC10062457 DOI: 10.3389/fphar.2023.1067422] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Respiratory diseases remain a major health concern worldwide because they subject patients to considerable financial and psychosocial burdens and result in a high rate of morbidity and mortality. Although significant progress has been made in understanding the underlying pathologic mechanisms of severe respiratory diseases, most therapies are supportive, aiming to mitigate symptoms and slow down their progressive course but cannot improve lung function or reverse tissue remodeling. Mesenchymal stromal cells (MSCs) are at the forefront of the regenerative medicine field due to their unique biomedical potential in promoting immunomodulation, anti-inflammatory, anti-apoptotic and antimicrobial activities, and tissue repair in various experimental models. However, despite several years of preclinical research on MSCs, therapeutic outcomes have fallen far short in early-stage clinical trials for respiratory diseases. This limited efficacy has been associated with several factors, such as reduced MSC homing, survival, and infusion in the late course of lung disease. Accordingly, genetic engineering and preconditioning methods have emerged as functional enhancement strategies to potentiate the therapeutic actions of MSCs and thus achieve better clinical outcomes. This narrative review describes various strategies that have been investigated in the experimental setting to functionally potentiate the therapeutic properties of MSCs for respiratory diseases. These include changes in culture conditions, exposure of MSCs to inflammatory environments, pharmacological agents or other substances, and genetic manipulation for enhanced and sustained expression of genes of interest. Future directions and challenges in efficiently translating MSC research into clinical practice are discussed.
Collapse
Affiliation(s)
- Miquéias Lopes-Pacheco
- Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
| | - Patricia R. M. Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
| |
Collapse
|
|
12
|
Li K, Wang T, Li R, Xue F, Zeng G, Zhang J, Ma Y, Feng L, Kang YJ. Dose-specific efficacy of adipose-derived mesenchymal stem cells in septic mice. Stem Cell Res Ther 2023; 14:32. [PMID: 36804962 PMCID: PMC9940377 DOI: 10.1186/s13287-023-03253-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 02/09/2023] [Indexed: 02/21/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) therapy for sepsis has been extensively studied in the past decade; however, the treatment regimen and mechanism of action of MSCs remain elusive. Here, we attempted to understand the efficacy and mechanism of action of MSCs on rescuing mice with sepsis. METHODS A mouse model of sepsis was produced by cecal ligation and puncture (CLP). Allogeneic adipose-derived MSCs (ADSCs) were administered by intravenous infusion at 6 h after CLP, and dose-related effects of ADSCs on these mice were determined by survival rate, histopathological changes, biochemical and coagulation parameters, bacterial load, and plasma levels of endotoxin and inflammatory cytokines. The tissue distribution of intravenously infused ADSCs in septic mice was investigated by pre-labeling ADSCs with the lipophilic membrane dye PKH26. RNA sequencing analysis was performed to assess the transcriptional changes in peripheral blood mononuclear cells (PBMCs) and the liver. RESULTS A significant therapeutic effect of ADSCs at a dose of 2 × 107 cells/kg in septic mice was evidenced by a remarkable reduction in mortality (35.89% vs. 8.89% survival rate), blood bacterial burden, systemic inflammation, and multiple organ damage. In contrast, ADSCs at a lower dose (1 × 107 cells/kg) failed to achieve any beneficial outcomes, while ADSCs at a higher dose (4 × 107 cells/kg) caused more early death within 24 h after CLP, retaining a steady survival rate of 21.42% thereafter. PKH26-labeled ADSCs were predominantly localized in the lungs of septic mice after intravenous infusion, with only a smaller proportion of PKH26-positive signals appearing in the liver and spleen. RNA sequencing analysis identified that insufficient phagocytic activity of PBMCs in addition to a hyperactivation of the hepatic immune response was responsible for the ineffectiveness of low-dose ADSCs therapy, and acute death caused by high-dose ADSCs infusion was associated with impaired coagulation signaling in PBMCs and exacerbated hepatic hypoxic injury. CONCLUSIONS Our findings demonstrate a dose-specific effect of ADSCs on the treatment of sepsis due to dose-related interactions between exogenous stem cells and the host's microenvironment. Therefore, a precise dosing regimen is a prerequisite for ADSCs therapy for sepsis.
Collapse
Affiliation(s)
- Kui Li
- grid.412901.f0000 0004 1770 1022Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041 China
| | - Tao Wang
- grid.412901.f0000 0004 1770 1022Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041 China ,grid.13291.380000 0001 0807 1581Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, Sichuan University West China Hosipital, Chengdu, Sichuan 610041 China
| | - Rui Li
- grid.412901.f0000 0004 1770 1022Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041 China
| | - Fulai Xue
- grid.412901.f0000 0004 1770 1022Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041 China
| | - Guodan Zeng
- grid.412901.f0000 0004 1770 1022Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041 China
| | - Jingyao Zhang
- grid.412901.f0000 0004 1770 1022Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041 China
| | - Yuan Ma
- grid.412901.f0000 0004 1770 1022Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041 China
| | - Li Feng
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan, 610041, China.
| | - Y. James Kang
- grid.412901.f0000 0004 1770 1022Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041 China ,grid.267301.10000 0004 0386 9246Memphis Institute of Regenerative Medicine, University of Tennessee Health Science Center, Memphis, TN 38163 USA
| |
Collapse
|
|
13
|
Tan MI, Alfarafisa NM, Septiani P, Barlian A, Firmansyah M, Faizal A, Melani L, Nugrahapraja H. Potential Cell-Based and Cell-Free Therapy for Patients with COVID-19. Cells 2022; 11:2319. [PMID: 35954162 PMCID: PMC9367488 DOI: 10.3390/cells11152319] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/20/2022] [Accepted: 07/26/2022] [Indexed: 02/01/2023] Open
Abstract
Since it was first reported, the novel coronavirus disease 2019 (COVID-19) remains an unresolved puzzle for biomedical researchers in different fields. Various treatments, drugs, and interventions were explored as treatments for COVID. Nevertheless, there are no standard and effective therapeutic measures. Meanwhile, mesenchymal stem cell (MSC) therapy offers a new approach with minimal side effects. MSCs and MSC-based products possess several biological properties that potentially alleviate COVID-19 symptoms. Generally, there are three classifications of stem cell therapy: cell-based therapy, tissue engineering, and cell-free therapy. This review discusses the MSC-based and cell-free therapies for patients with COVID-19, their potential mechanisms of action, and clinical trials related to these therapies. Cell-based therapies involve the direct use and injection of MSCs into the target tissue or organ. On the other hand, cell-free therapy uses secreted products from cells as the primary material. Cell-free therapy materials can comprise cell secretomes and extracellular vesicles. Each therapeutic approach possesses different benefits and various risks. A better understanding of MSC-based and cell-free therapies is essential for supporting the development of safe and effective COVID-19 therapy.
Collapse
Affiliation(s)
- Marselina Irasonia Tan
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Nayla Majeda Alfarafisa
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang 45363, Indonesia;
| | - Popi Septiani
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Anggraini Barlian
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Mochamad Firmansyah
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Ahmad Faizal
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Lili Melani
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Husna Nugrahapraja
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| |
Collapse
|
|
14
|
Yang K, Lu R, Lu J, Fan S, Zhang Q, Lou Z, Ma Y, Lu G, Pan R, Zhang J. Phenotypic and Functional Characterizations of Mesenchymal Stem/Stromal Cells Isolated From Human Cranial Bone Marrow. Front Neurosci 2022; 16:909256. [PMID: 35747205 PMCID: PMC9209782 DOI: 10.3389/fnins.2022.909256] [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: 03/31/2022] [Accepted: 05/17/2022] [Indexed: 11/29/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are adult stem cells that were originally isolated from bone marrow. In contrast to long bone-derived MSCs that have been extensively characterized, our knowledge regarding to MSCs isolated from flat bones (e.g., cranial bones) remain less clear. In this study, MSCs were purified from human cranial bone marrow (CB-MSCs) and their transdifferentiation capacity and immunomodulatory functions were further characterized. Phenotypic analysis of CB-MSCs demonstrated high expression of CD73, CD90, and CD105 while negative for CD14, CD34, and HLA-DR. Further in vitro differentiation assay shown that CB-MSCs capable of differentiating into cell types of mesenchymal origin (i.e., adipocytes, osetoblasts, and chondrocytes) and collectively, these results indicated that cells isolated from cranial bone marrow in this study are bona fide MSCs according to the minimal criteria proposed by the International Society for Cellular Therapy. Following in vitro expansion, single colony-derived CB-MSCs (scCB-MSCs) were obtained and confocal microscopy analysis further revealed functional heterogeneity within primary CB-MSCs. Specifically, obtained scCB-MSCs exhibited GABA progenitor features, as determined by olig2 and nestin. As expect, scCB-MSCs were readily induced to differentiate into GABAergic neuron-like cells. Furthermore, immunomodulatory roles of scCB-MSCs were evaluated following co-culture with human peripheral blood lymphocytes and results shown that co-culturing with scCB-MSCs significantly suppressed lymphocyte proliferation and promoted differentiation of lymphocytes into regulatory T cells but not Th1/Th17 phenotype. Overall, our results indicated that CB-MSCs exhibited clonal heterogeneity with marked propensity to differentiate into neural-like cells and this might represent promising candidates for the treatment of neurodegenerative diseases.
Collapse
Affiliation(s)
- Kaichuang Yang
- Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China
- Center for Rehabilitation Medicine, Department of Neurosurgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Ruijie Lu
- The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Jianan Lu
- Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China
| | - Shucai Fan
- Center for Rehabilitation Medicine, Department of Neurosurgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Qiang Zhang
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Hangzhou, China
- Institute for Cell-Based Drug Development of Zhejiang Province, S-Evans Biosciences, Hangzhou, China
| | - Zijian Lou
- The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Yuyuan Ma
- Center for Rehabilitation Medicine, Department of Neurosurgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Gang Lu
- Center for Rehabilitation Medicine, Department of Neurosurgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Ruolang Pan
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Hangzhou, China
- Institute for Cell-Based Drug Development of Zhejiang Province, S-Evans Biosciences, Hangzhou, China
- *Correspondence: Ruolang Pan
| | - Jianmin Zhang
- Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China
- Jianmin Zhang
| |
Collapse
|
|
15
|
Immunomodulation via MyD88-NFκB Signaling Pathway from Human Umbilical Cord-Derived Mesenchymal Stem Cells in Acute Lung Injury. Int J Mol Sci 2022; 23:ijms23105295. [PMID: 35628107 PMCID: PMC9141460 DOI: 10.3390/ijms23105295] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/08/2022] [Accepted: 05/08/2022] [Indexed: 01/01/2023] Open
Abstract
Excess inflammatory processes play a key detrimental role in the pathophysiology of acute lung injury (ALI). Mesenchymal stem cells (MSCs) were reported to be beneficial to ALI, but the underlying mechanisms have not been completely understood. The present study aimed to examine the involvement of MyD88−NFκB signaling in the immunomodulation of MSCs in mice with lipopolysaccharides (LPS)-induced ALI. We found that serum concentrations of IL-6, TNF-α, MCP-1, IL-1β, and IL-8 were significantly decreased at 6 h after LPS-induced ALI in the MSC group (p < 0.05). For each of the five cytokines, the serum concentration of each individual mouse in either group declined to a similar level at 48 h. The intensity of lung injury lessened in the MSC group, as shown by histopathology and lung injury scores (p < 0.001). The expressions of MyD88 and phospho-NFκB in the lung tissue were significantly decreased in mice receiving MSCs as measured by Western blotting and immunohistochemistry. Our data demonstrated that human umbilical cord-derived MSCs could effectively alleviate the cytokine storm in mice after LPS-induced ALI and attenuated lung injury. Firstly, we documented the correlation between the down-regulation of MyD88−NFκB signaling and immunomodulatory effects of MSCs in the situation of ALI.
Collapse
|
|
16
|
Ge L, Zhao J, Deng H, Chen C, Hu Z, Zeng L. Effect of Bone Marrow Mesenchymal Stromal Cell Therapies in Rodent Models of Sepsis: A Meta-Analysis. Front Immunol 2022; 12:792098. [PMID: 35046951 PMCID: PMC8761857 DOI: 10.3389/fimmu.2021.792098] [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: 10/12/2021] [Accepted: 12/08/2021] [Indexed: 12/09/2022] Open
Abstract
Background Multiple preclinical studies have demonstrated that bone‐marrow derived mesenchymal stromal (stem) cells [MSC(M)] positively influence the severity of sepsis symptoms and mortality in rodent models. However, this remains an inconclusive finding. Objective To review the effect of naïve MSC(M) in rodent models of sepsis. Methods The PubMed, EMBASE, and Web of Science databases were searched up to August 31, 2021. Inclusion criteria according to PICOS criteria were as follows: (1) population: rodents; (2) intervention: unmodified MSC(M); (3) comparison: not specified; (4) primary outcome: the effects of MSC(M) cell therapy on the mortality of rodent models of sepsis and endotoxemia; (5) study: experimental studies. Multiple prespecified subgroup and meta-regression analysis were conducted. Following quality assessment, random effects models were used for this meta-analysis.The inverse variance method of the fixed effects model was used to calculate the pooled odds ratios (ORs) and their 95% confidence intervals (CIs). Results twenty-four animal studies met the inclusion criteria. Our results revealed an overall OR difference between animals treated with naïve MSC(M) and controls for mortality rate was 0.34(95% confidence interval: 0.27-0.44; P < 0.0001). Significant heterogeneity among studies was observed. Conclusions The findings of this meta-analysis suggest that naïve MSC(M) therapy decreased mortality in rodent models of sepsis. Additionally, we identified several key knowledge gaps, including the lack of large animal studies and uncertainty regarding the optimal dose of MSC(M) transplantation in sepsis. Before MSC(M) treatment can advance to clinical trials, these knowledge gaps must be addressed.
Collapse
Affiliation(s)
- Lite Ge
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Provincical Key Laboratory of Neurorestoratology, The Second Affiliated Hospital, Hunan Normal University, Changsha, China
| | - Jing Zhao
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Huiyin Deng
- Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Chunli Chen
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhiping Hu
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Liuwang Zeng
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
17
|
Shaw TD, Krasnodembskaya AD, Schroeder GN, Zumla A, Maeurer M, O’Kane CM. Mesenchymal Stromal Cells: an Antimicrobial and Host-Directed Therapy for Complex Infectious Diseases. Clin Microbiol Rev 2021; 34:e0006421. [PMID: 34612662 PMCID: PMC8510528 DOI: 10.1128/cmr.00064-21] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
There is an urgent need for new antimicrobial strategies for treating complex infections and emerging pathogens. Human mesenchymal stromal cells (MSCs) are adult multipotent cells with antimicrobial properties, mediated through direct bactericidal activity and modulation of host innate and adaptive immune cells. More than 30 in vivo studies have reported on the use of human MSCs for the treatment of infectious diseases, with many more studies of animal MSCs in same-species models of infection. MSCs demonstrate potent antimicrobial effects against the major classes of human pathogens (bacteria, viruses, fungi, and parasites) across a wide range of infection models. Mechanistic studies have yielded important insight into their immunomodulatory and bactericidal activity, which can be enhanced through various forms of preconditioning. MSCs are being investigated in over 80 clinical trials for difficult-to-treat infectious diseases, including sepsis and pulmonary, intra-abdominal, cutaneous, and viral infections. Completed trials consistently report MSCs to be safe and well tolerated, with signals of efficacy against some infectious diseases. Although significant obstacles must be overcome to produce a standardized, affordable, clinical-grade cell therapy, these studies suggest that MSCs may have particular potential as an adjunct therapy in complex or resistant infections.
Collapse
Affiliation(s)
- Timothy D. Shaw
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Anna D. Krasnodembskaya
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Gunnar N. Schroeder
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Alimuddin Zumla
- Center for Clinical Microbiology, Division of Infection and Immunity, University College London, NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom
| | - Markus Maeurer
- Immunosurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Department of Oncology and Haematology, Krankenhaus Nordwest, Frankfurt, Germany
| | - Cecilia M. O’Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| |
Collapse
|
|
18
|
Xu Z, Huang Y, Zhou J, Deng X, He W, Liu X, Li Y, Zhong N, Sang L. Current Status of Cell-Based Therapies for COVID-19: Evidence From Mesenchymal Stromal Cells in Sepsis and ARDS. Front Immunol 2021; 12:738697. [PMID: 34659231 PMCID: PMC8517471 DOI: 10.3389/fimmu.2021.738697] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/13/2021] [Indexed: 12/29/2022] Open
Abstract
The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted the urgent need for novel therapies. Cell-based therapies, primarily using mesenchymal stromal cells (MSCs), have demonstrated safety and potential efficacy in the treatment of critical illness, particularly sepsis and acute respiratory distress syndrome (ARDS). However, there are limited preclinical data for MSCs in COVID-19. Recent studies have shown that MSCs could decrease inflammation, improve lung permeability, enhance microbe and alveolar fluid clearance, and promote lung epithelial and endothelial repair. In addition, MSC-based therapy has shown promising effects in preclinical studies and phase 1 clinical trials in sepsis and ARDS. Here, we review recent advances related to MSC-based therapy in the context of sepsis and ARDS and evaluate the potential value of MSCs as a therapeutic strategy for COVID-19.
Collapse
Affiliation(s)
- Zhiheng Xu
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Yongbo Huang
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Jianmeng Zhou
- School of Public Health, Southern Medical University, Guangzhou, China
| | - Xiumei Deng
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Weiqun He
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Xiaoqing Liu
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Yimin Li
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Nanshan Zhong
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Ling Sang
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China.,Guangzhou Laboratory, Guangzhou, China
| |
Collapse
|
|
19
|
Wang M, Zhou T, Zhang Z, Liu H, Zheng Z, Xie H. Current therapeutic strategies for respiratory diseases using mesenchymal stem cells. MedComm (Beijing) 2021; 2:351-380. [PMID: 34766151 PMCID: PMC8554668 DOI: 10.1002/mco2.74] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have a great potential to proliferate, undergo multi-directional differentiation, and exert immunoregulatory effects. There is already much enthusiasm for their therapeutic potentials for respiratory inflammatory diseases. Although the mechanism of MSCs-based therapy has been well explored, only a few articles have summarized the key advances in this field. We hereby provide a review over the latest progresses made on the MSCs-based therapies for four types of inflammatory respiratory diseases, including idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, and the uncovery of their underlying mechanisms from the perspective of biological characteristics and functions. Furthermore, we have also discussed the advantages and disadvantages of the MSCs-based therapies and prospects for their optimization.
Collapse
Affiliation(s)
- Ming‐yao Wang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Ting‐yue Zhou
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐dong Zhang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hao‐yang Liu
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐yao Zheng
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hui‐qi Xie
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| |
Collapse
|
|
20
|
Ahmed E, Saleh T, Xu M. Recellularization of Native Tissue Derived Acellular Scaffolds with Mesenchymal Stem Cells. Cells 2021; 10:cells10071787. [PMID: 34359955 PMCID: PMC8304639 DOI: 10.3390/cells10071787] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/03/2021] [Accepted: 07/12/2021] [Indexed: 12/22/2022] Open
Abstract
The functionalization of decellularized scaffolds is still challenging because of the recellularization-related limitations, including the finding of the most optimal kind of cell(s) and the best way to control their distribution within the scaffolds to generate native mimicking tissues. That is why researchers have been encouraged to study stem cells, in particular, mesenchymal stem cells (MSCs), as alternative cells to repopulate and functionalize the scaffolds properly. MSCs could be obtained from various sources and have therapeutic effects on a wide range of inflammatory/degenerative diseases. Therefore, in this mini-review, we will discuss the benefits using of MSCs for recellularization, the factors affecting their efficiency, and the drawbacks that may need to be overcome to generate bioengineered transplantable organs.
Collapse
Affiliation(s)
- Ebtehal Ahmed
- Department of Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut 71515, Egypt;
| | - Tarek Saleh
- Department of Animal Surgery, Faculty of Veterinary Medicine, Assiut University, Assiut 71515, Egypt;
| | - Meifeng Xu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA
- Correspondence: or ; Tel.: +1-513-558-4725; Fax: +1-513-558-2141
| |
Collapse
|
|
21
|
Pezzanite LM, Chow L, Johnson V, Griffenhagen GM, Goodrich L, Dow S. Toll-like receptor activation of equine mesenchymal stromal cells to enhance antibacterial activity and immunomodulatory cytokine secretion. Vet Surg 2021; 50:858-871. [PMID: 33797775 DOI: 10.1111/vsu.13628] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 02/10/2021] [Accepted: 03/18/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To evaluate effects of Toll-like and nucleotide-binding oligomerization domain (NOD)-like receptor (TLR, NLR) ligand stimulation of equine mesenchymal stromal cells (MSCs) on antibacterial and immunomodulatory properties in vitro. STUDY DESIGN Controlled laboratory study. SAMPLE POPULATION Equine bone-marrow-derived MSCs (three horses). METHODS MSCs were stimulated with TLR (polyinosinic:polycytidylic acid [pIC] and lipopolysaccharide [LPS]) and NLR agonists (γ-d-Glu-mDAP [IE-DAP]) for 2 h, and plated at 1 × 105 cells/well 24 h. MSC-conditioned media (MSC-CM) were collected and assessed for antimicrobial peptide cathelicidin/LL-37 production, bactericidal action against multidrug-resistant planktonic and biofilm Staphylococcus aureus and neutrophil phagocytosis. Bacterial growth was measured by plating bacteria and counting viable colonies, reading culture absorbance, and live-dead staining with confocal microscopy imaging. Following initial comparison of activating stimuli, TLR3-agonist pIC protocols (cell density during activation and plating, culture time, %serum) were further optimized for bactericidal activity and secretion of interleukin-8 (IL-8), monocyte-chemoattractant-protein (MCP-1), and cathelicidin/LL37. RESULTS MSCs stimulation with pIC (p = .004) and IE-DAP (p = .03) promoted increased bactericidal activity, evidenced by reduced viable planktonic colony counts. PIC stimulation (2 × 106 cells/ml, 2 h, 10 μg/ml) further suppressed biofilm formation (p = .001), enhanced neutrophil bacterial phagocytosis (p = .009), increased MCP-1 secretion (p < .0001), and enhanced cathelicidin/LL-37 production, which was apparent when serum concentration in media was reduced to 1% (p = .01) and 2.5% (p = .05). CONCLUSION TLR-3 pIC MSCs activation was most effective to enhance antibacterial and cytokine responses, which were affected by serum reduction. CLINICAL SIGNIFICANCE In vitro TLR-3 activation of equine MSCs tested here may be a strategy to improve antibacterial properties of MSCs to treat antibiotic-resistant infections.
Collapse
Affiliation(s)
- Lynn M Pezzanite
- Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Colorado, USA
| | - Lyndah Chow
- Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Colorado, USA
| | - Valerie Johnson
- Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Colorado, USA
| | - Gregg M Griffenhagen
- Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Colorado, USA
| | - Laurie Goodrich
- Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Colorado, USA
| | - Steven Dow
- Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Colorado, USA
| |
Collapse
|
|
22
|
Wang WD, Yang XR, Guo MF, Pan ZF, Shang M, Qiu MJ, Wu JY, Jia J, Liang YL, Zheng WT, Xu JF, Chen GH. Up-regulation of BTLA expression in myeloid dendritic cells associated with the treatment outcome of neonatal sepsis. Mol Immunol 2021; 134:129-140. [PMID: 33773156 DOI: 10.1016/j.molimm.2021.03.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 02/21/2021] [Accepted: 03/04/2021] [Indexed: 11/17/2022]
Abstract
Dentritic cells (DCs) dysfunction has been verified detrimental for sepsis and B and T lymphocyte attenuator (BTLA) is an immune-regulatory receptor shown to be associated with DCs dysfunction. However, the role of BTLA expression in myeloid DCs (mDCs) in neonatal sepsis is unknown. In the current study, we found BTLA-expressing mDCs were elevated in neonates with sepsis and the BTLA expression level in mDCs was positively correlated to the severity of sepsis. The presence of BTLA negatively regulated the phagocytosis capacity and bactericidal ability of mDCs as well as the maturation markers expression of mDCs. Our data also showed BTLA+mDCs shifted into an anti-inflammatory phenotype with decreased expression of IL-6, TNF-α and IL-12, but increased IL-10. in addition, we found BTLA expression indeedly altered the mDCs allo-stimulatory capacity. Therefore, BTLA expression in mDCs could be a useful predictive marker for neonatal sepsis and targeting BTLA expression in mDCs may be a new therapeutic strategy.
Collapse
Affiliation(s)
- Wan-Dang Wang
- Department of Clinical Medicine Laboratory, Affiliated Xiaolan Hospital, Southern Medical University, China
| | - Xu-Ran Yang
- Department of Clinical Medicine Laboratory, Affiliated Xiaolan Hospital, Southern Medical University, China
| | - Ming-Fa Guo
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, China
| | - Zhi-Feng Pan
- Department of Clinical Medicine Laboratory, Affiliated Xiaolan Hospital, Southern Medical University, China
| | - Mei Shang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Ming-Jin Qiu
- Department of Clinical Medicine Laboratory, Affiliated Xiaolan Hospital, Southern Medical University, China
| | - Jing-Yi Wu
- Department of Clinical Medicine Laboratory, Affiliated Xiaolan Hospital, Southern Medical University, China
| | - Jing Jia
- Department of Clinical Medicine Laboratory, Children's Hospital Affiliated to Zhengzhou University, China
| | - Ying-Liang Liang
- Department of Clinical Medicine Laboratory, Affiliated Xiaolan Hospital, Southern Medical University, China
| | - Wen-Ting Zheng
- Department of Clinical Medicine Laboratory, Affiliated Xiaolan Hospital, Southern Medical University, China
| | - Jun-Fa Xu
- Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical University, Dongguan, China
| | - Guang-Hui Chen
- Department of Clinical Medicine Laboratory, Affiliated Xiaolan Hospital, Southern Medical University, China.
| |
Collapse
|
|
23
|
Chen R, Xie Y, Zhong X, Chen F, Gong Y, Wang N, Wang D. MSCs derived from amniotic fluid and umbilical cord require different administration schemes and exert different curative effects on different tissues in rats with CLP-induced sepsis. Stem Cell Res Ther 2021; 12:164. [PMID: 33676566 PMCID: PMC7936453 DOI: 10.1186/s13287-021-02218-8] [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: 11/05/2020] [Accepted: 02/09/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are derived from multiple tissues, including amniotic fluid (AF-MSCs) and the umbilical cord (UC-MSCs). Although the therapeutic effect of MSCs on sepsis is already known, researchers have not determined whether the cells from different sources require different therapeutic schedules or exert different curative effects. We assessed the biofunction of the administration of AF-MSCs and UC-MSCs in rats with caecal ligation and puncture (CLP)-induced sepsis. METHODS CLP was used to establish a disease model of sepsis in rats, and intravenous tail vein administration of AF-MSCs and UC-MSCs was performed to treat sepsis at 6 h after CLP. Two phases of animal experiments were implemented using MSCs harvested in saline with or without filtration. The curative effect was measured by determining the survival rate. Further effects were assessed by measuring proinflammatory cytokine levels, the plasma coagulation index, tissue histology and the pathology of the lung, liver and kidney. RESULTS We generated rats with medium-grade sepsis with a 30-40% survival rate to study the curative effects of AF-MSCs and UC-MSCs. MSCs reversed CLP-induced changes in proinflammatory cytokine levels and coagulation activation. MSCs ameliorated CLP-induced histological and pathological changes in the lung, liver and kidney. AF-MSCs and UC-MSCs functioned differently in different tissues; UC-MSCs performed well in reducing the upregulation of inflammatory cytokine levels in the lungs and inhibiting the inflammatory cell infiltration into the liver capsule, while AF-MSCs performed well in inhibiting cell death in the kidneys and reducing the plasma blood urea nitrogen (BUN) level, an indicator of renal function. CONCLUSIONS Our studies suggest the safety and efficacy of AF-MSCs and UC-MSCs in the treatment of CLP-induced sepsis in rats and show that the cells potentially exert different curative effects on the main sepsis-affected tissues.
Collapse
Affiliation(s)
- Rui Chen
- Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China.,Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China
| | - Yingjun Xie
- Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China.,Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China
| | - Xuan Zhong
- Medical Intensive Care Unit, Guangdong Women and Children Hospital, Guangzhou, 510150, Guangdong, China
| | - Fei Chen
- Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China.,Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China
| | - Yu Gong
- Central Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China
| | - Na Wang
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China
| | - Ding Wang
- Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China. .,Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China.
| |
Collapse
|
|
24
|
El-Jawhari JJ, El-Sherbiny Y, McGonagle D, Jones E. Multipotent Mesenchymal Stromal Cells in Rheumatoid Arthritis and Systemic Lupus Erythematosus; From a Leading Role in Pathogenesis to Potential Therapeutic Saviors? Front Immunol 2021; 12:643170. [PMID: 33732263 PMCID: PMC7959804 DOI: 10.3389/fimmu.2021.643170] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/29/2021] [Indexed: 12/15/2022] Open
Abstract
The pathogenesis of the autoimmune rheumatological diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is complex with the involvement of several immune cell populations spanning both innate and adaptive immunity including different T-lymphocyte subsets and monocyte/macrophage lineage cells. Despite therapeutic advances in RA and SLE, some patients have persistent and stubbornly refractory disease. Herein, we discuss stromal cells' dual role, including multipotent mesenchymal stromal cells (MSCs) also used to be known as mesenchymal stem cells as potential protagonists in RA and SLE pathology and as potential therapeutic vehicles. Joint MSCs from different niches may exhibit prominent pro-inflammatory effects in experimental RA models directly contributing to cartilage damage. These stromal cells may also be key regulators of the immune system in SLE. Despite these pro-inflammatory roles, MSCs may be immunomodulatory and have potential therapeutic value to modulate immune responses favorably in these autoimmune conditions. In this review, the complex role and interactions between MSCs and the haematopoietically derived immune cells in RA and SLE are discussed. The harnessing of MSC immunomodulatory effects by contact-dependent and independent mechanisms, including MSC secretome and extracellular vesicles, is discussed in relation to RA and SLE considering the stromal immune microenvironment in the diseased joints. Data from translational studies employing MSC infusion therapy against inflammation in other settings are contextualized relative to the rheumatological setting. Although safety and proof of concept studies exist in RA and SLE supporting experimental and laboratory data, robust phase 3 clinical trial data in therapy-resistant RA and SLE is still lacking.
Collapse
Affiliation(s)
- Jehan J El-Jawhari
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.,Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Yasser El-Sherbiny
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.,Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Dennis McGonagle
- Faculty of Medicine and Health, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom.,The National Institute for Health Research Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, United Kingdom
| | - Elena Jones
- Faculty of Medicine and Health, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom.,The National Institute for Health Research Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, United Kingdom
| |
Collapse
|
|
25
|
Gorman E, Millar J, McAuley D, O'Kane C. Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential. Expert Rev Respir Med 2020; 15:301-324. [PMID: 33172313 DOI: 10.1080/17476348.2021.1848555] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Mesenchymal stromal (stem) cell (MSC) therapies are emerging as a promising therapeutic intervention in patients with Acute Respiratory Distress Syndrome (ARDS) and sepsis due to their reparative, immunomodulatory, and antimicrobial properties.Areas covered: This review provides an overview of Mesenchymal stromal cells (MSCs) and their mechanisms of effect in ARDS and sepsis. The preclinical and clinical evidence to support MSC therapy in ARDS and sepsis is discussed. The potential for MSC therapy in COVID-19 ARDS is discussed with insights from respiratory viral models and early clinical reports of MSC therapy in COVID-19. Strategies to optimize the therapeutic potential of MSCs in ARDS and sepsis are considered including preconditioning, altered gene expression, and alternative cell-free MSC-derived products, such as extracellular vesicles and conditioned medium.Expert opinion: MSC products present considerable therapeutic promise for ARDS and sepsis. Preclinical investigations report significant benefits and early phase clinical studies have not highlighted safety concerns. Optimization of MSC function in preclinical models of ARDS and sepsis has enhanced their beneficial effects. MSC-derived products, as cell-free alternatives, may provide further advantages in this field. These strategies present opportunity for the clinical development of MSCs and MSC-derived products with enhanced therapeutic efficacy.
Collapse
Affiliation(s)
- Ellen Gorman
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
| | - Jonathan Millar
- Division of Functional Genetics and Development, Roslin Institute, University of Edinburgh, Edinburgh, UK
| | - Danny McAuley
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
| | - Cecilia O'Kane
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
| |
Collapse
|
|
26
|
Li W, Chen W, Huang S, Yao G, Tang X, Sun L. Mesenchymal stem cells prevent overwhelming inflammation and reduce infection severity via recruiting CXCR3 + regulatory T cells. Clin Transl Immunology 2020; 9:e1181. [PMID: 33014369 PMCID: PMC7526004 DOI: 10.1002/cti2.1181] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 08/24/2020] [Accepted: 08/25/2020] [Indexed: 12/17/2022] Open
Abstract
Objectives Mesenchymal stem cells (MSCs) have shown great potential in treating autoimmune diseases (ADs). Unlike the traditional immunosuppressants, which inadvertently impair patients' antimicrobial immunity, MSCs reduce the incidence and duration of respiratory infection. However, the underlying mechanisms are unknown. Methods To investigate how MSCs regulate the lung immunity and improve the defence against respiratory infection, we infected MSC‐treated wild‐type and lupus‐prone mice with Haemophilus influenzae intranasally and determined the clearance of bacteria. Tissue damage and inflammatory cytokines were measured by H&E staining and ELISA separately. Immune cell subsets in the tissues were analysed by flow cytometry. Results MSC pretreatment prevented overwhelming inflammation and accelerated bacterial clearance in both wild‐type and lupus‐prone mice. Tregs increased dramatically in the lung after MSC treatment. Adoptive transfer of Tregs isolated from MSC‐treated mice offered similar protection, while deletion of Tregs abrogated the protective effects of MSCs. The majority of the intravenously injected MSCs were engulfed by lung phagocytes, which in turn produced CXCL9 and CXCL10 and recruited tremendous CXCR3+ Tregs into the lung. Compared with their CXCR3− counterparts, CXCR3+ Tregs displayed enhanced proliferation and stronger inhibitory functions. Neutralisation of CXCL9 and CXCL10 significantly downregulated the migration of CXCR3+ Tregs and eliminated the benefits of MSC pretreatment. Conclusion Here, we showed that by recruiting CXCR3+ Tregs, MSC treatment restricted the overactivation of inflammatory responses and prevented severe symptoms caused by infection. By discovering this novel property of MSCs, our study sheds light on optimising long‐term immunosuppressive regimen for autoimmune diseases and other immune disorders.
Collapse
Affiliation(s)
- Wenchao Li
- Department of Rheumatology and Immunology The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China
| | - Weiwei Chen
- Department of Rheumatology and Immunology The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China
| | - Saisai Huang
- Department of Rheumatology and Immunology The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China
| | - Genhong Yao
- Department of Rheumatology and Immunology The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China
| | - Xiaojun Tang
- Department of Rheumatology and Immunology The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China
| | - Lingyun Sun
- Department of Rheumatology and Immunology The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China
| |
Collapse
|
|
27
|
Byrnes D, Masterson CH, Artigas A, Laffey JG. Mesenchymal Stem/Stromal Cells Therapy for Sepsis and Acute Respiratory Distress Syndrome. Semin Respir Crit Care Med 2020; 42:20-39. [PMID: 32767301 DOI: 10.1055/s-0040-1713422] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sepsis and acute respiratory distress syndrome (ARDS) constitute devastating conditions with high morbidity and mortality. Sepsis results from abnormal host immune response, with evidence for both pro- and anti-inflammatory activation present from the earliest phases. The "proinflammatory" response predominates initially causing host injury, with later-phase sepsis characterized by immune cell hypofunction and opportunistic superinfection. ARDS is characterized by inflammation and disruption of the alveolar-capillary membrane leading to injury and lung dysfunction. Sepsis is the most common cause of ARDS. Approximately 20% of deaths worldwide in 2017 were due to sepsis, while ARDS occurs in over 10% of all intensive care unit patients and results in a mortality of 30 to 45%. Given the fact that sepsis and ARDS share some-but not all-underlying pathophysiologic injury mechanisms, the lack of specific therapies, and their frequent coexistence in the critically ill, it makes sense to consider therapies for both conditions together. In this article, we will focus on the therapeutic potential of mesenchymal stem/stromal cells (MSCs). MSCs are available from several tissues, including bone marrow, umbilical cord, and adipose tissue. Allogeneic administration is feasible, an important advantage for acute conditions like sepsis or ARDS. They possess diverse mechanisms of action of relevance to sepsis and ARDS, including direct and indirect antibacterial actions, potent effects on the innate and adaptive response, and pro-reparative effects. MSCs can be preactivated thereby potentiating their effects, while the use of their extracellular vesicles can avoid whole cell administration. While early-phase clinical trials suggest safety, considerable challenges exist in moving forward to phase III efficacy studies, and to implementation as a therapy should they prove effective.
Collapse
Affiliation(s)
- Declan Byrnes
- Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.,Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Claire H Masterson
- Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.,Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Antonio Artigas
- Critical Care Center, Corporació Sanitaria Parc Tauli, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain
| | - John G Laffey
- Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.,Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland.,Department of Anaesthesia, SAOLTA University Health Group, Galway University Hospitals, Galway, Ireland
| |
Collapse
|
|
28
|
Sun XY, Ding XF, Liang HY, Zhang XJ, Liu SH, Bing-Han, Duan XG, Sun TW. Efficacy of mesenchymal stem cell therapy for sepsis: a meta-analysis of preclinical studies. Stem Cell Res Ther 2020; 11:214. [PMID: 32493435 PMCID: PMC7268531 DOI: 10.1186/s13287-020-01730-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/28/2020] [Accepted: 05/13/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Multiple studies have reported that mesenchymal stem cell (MSC) therapy has beneficial effects in experimental models of sepsis. However, this finding remains inconclusive. This study was performed to systematically determine the connection between MSC therapy and mortality in sepsis animal models by pooling and analyzing data from newly published studies. METHODS A detailed search of related studies from 2009 to 2019 was conducted in four databases, including MEDLINE, EMBASE, Cochrane Library, and Web of Science. After browsing and filtering out articles that met the inclusion criteria for statistical analysis, the inverse variance method of the fixed effects model was used to calculate the pooled odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS Twenty-nine animal studies, including 1266 animals, were identified. None of the studies was judged to have a low risk of bias. The meta-analysis demonstrated that MSC therapy was related to a significantly lower mortality rate (OR 0.29, 95% CI 0.22-0.38, P < 0.001). Subgroup analyses performed based on the MSC injection dose (< 1.0 × 106 cells, OR = 0.33, 95% CI 0.20-0.56, P < 0.001; 1.0 × 106 cells, OR = 0.24, 95% CI 0.16-0.35, P < 0.001) and injection time (< 1 h, OR = 0.24, 95% CI 0.13-0.45, P < 0.001; 1 h, OR = 0.28, 95% CI 0.17-0.46, P < 0.001) demonstrated that treatment with MSCs significantly reduced the mortality rate of animals with sepsis. CONCLUSION This up-to-date meta-analysis showed a connection between MSC therapy and lower mortality in sepsis animal models, supporting the potential therapeutic effect of MSC treatment in future clinical trials. The results in this study contradict a previous meta-analysis with regards to the ideal dose of MSC therapy. Thus, further research is required to support these findings.
Collapse
Affiliation(s)
- Xue-Yi Sun
- General ICU, Henan Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Key Laboratory of Sepsis, Zhengzhou, 450052 China
| | - Xian-Fei Ding
- General ICU, Henan Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Key Laboratory of Sepsis, Zhengzhou, 450052 China
| | - Huo-Yan Liang
- General ICU, Henan Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Key Laboratory of Sepsis, Zhengzhou, 450052 China
| | - Xiao-Juan Zhang
- General ICU, Henan Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Key Laboratory of Sepsis, Zhengzhou, 450052 China
| | - Shao-Hua Liu
- General ICU, Henan Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Key Laboratory of Sepsis, Zhengzhou, 450052 China
| | - Bing-Han
- General ICU, Henan Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Key Laboratory of Sepsis, Zhengzhou, 450052 China
| | - Xiao-Guang Duan
- General ICU, Henan Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Key Laboratory of Sepsis, Zhengzhou, 450052 China
| | - Tong-Wen Sun
- General ICU, Henan Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Key Laboratory of Sepsis, Zhengzhou, 450052 China
| |
Collapse
|
|
29
|
Zhang Y, Deng Z, Li Y, Yuan R, Yang M, Zhao Y, Wang L, Zhou F, Kang H. Mesenchymal Stem Cells Provide Neuroprotection by Regulating Heat Stroke-Induced Brain Inflammation. Front Neurol 2020; 11:372. [PMID: 32477247 PMCID: PMC7232542 DOI: 10.3389/fneur.2020.00372] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 04/14/2020] [Indexed: 01/01/2023] Open
Abstract
Heat stroke (HS) is the most acute type of heat illness accompanied with serious central nervous system (CNS) dysfunction. Despite the pathological process being clearly studied, effective treatment is deficient. Currently, mesenchymal stem cells (MSCs) have been demonstrated to have neuroprotective effects as there are no old ones. Thus, the purpose of the present study was to explore the neuroprotective effects and mechanisms of MSCs against HS-induced CNS injury. HS in rat models was induced by a high-temperature environment and treated with MSCs via the tail vein. The results demonstrated that MSC injection significantly reduced the mortality and inhibited the circulation inflammatory response. Moreover, the HS-induced neurological deficit and neuronic damage of the hippocampus were significantly ameliorated by MSC administration. In addition, MSC administration significantly restored astrocytes and inhibited cerebral inflammatory response. These results indicate that MSC infusion has therapeutic effects in HS of rats by regulating the circulation and cerebral inflammatory response. Moreover, astrocytes increased in MSC-treated HS rats when compared with the untreated ones. This may suggest a potential mechanism for HS prevention and therapy through MSC administration.
Collapse
Affiliation(s)
- Yu Zhang
- Department of Critical Care Medicine, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Zihui Deng
- Biochemistry Department of Graduate School, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Yun Li
- Department of Critical Care Medicine, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Rui Yuan
- Department of Critical Care Medicine, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Mengmeng Yang
- Department of Critical Care Medicine, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Yan Zhao
- Department of Critical Care Medicine, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Lu Wang
- Department of Critical Care Medicine, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Feihu Zhou
- Department of Critical Care Medicine, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Hongjun Kang
- Department of Critical Care Medicine, General Hospital of the Chinese People's Liberation Army, Beijing, China
| |
Collapse
|
|
30
|
Topcu Sarica L, Zibandeh N, Genç D, Gül F, Akkoç T, Kombak EF, Cinel L, Akkoç T, Cinel I. Immunomodulatory and Tissue-preserving Effects of Human Dental Follicle Stem Cells in a Rat Cecal Ligation and Perforation Sepsis Model. Arch Med Res 2020; 51:397-405. [PMID: 32334851 DOI: 10.1016/j.arcmed.2020.04.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 03/19/2020] [Accepted: 04/10/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Mesenchymal stem cells may be used for the treatment of sepsis. Dental follicle stem cells (DFSCs) are easily accessible but have not been studied in vivo or in clinical trials in sepsis models. AIM OF THE STUDY We aim to elucidate DFSC effects on host immunological functions in a rat cecal ligation and perforation (CLP) sepsis model. METHODS Adult male rats were categorized into group 1 (sham procedure SP), group 2 (SP + 1 × 106 DFSCs administered 0 h after SP), group 3 (CLP + saline), group 4 (CLP + 1 × 106 DFSCs administered 0 h after CLP), and group 5 (CLP + 1 × 106 DFSCs administered 4 h after CLP). Green fluorescent protein-labeled cells were used for imaging. Histopathological examination of ileal tissues was performed. RESULTS A significant increase in the percentage of CD4+/CD25+/Foxp3+ Treg cells in groups 4 and 5 occurred compared with that in group 3. No significant changes in CD3+/CD4+ helper T-cells and CD3+/CD8+ cytotoxic T-cells were observed. Treatment with DFSCs at 4 h significantly decreased the level of TNF-α compared with that in group 3. No significant changes in IL-10 levels and lymphocyte proliferation suppression were observed. During histopathological examination, no high scoring (Chiu scores: 3 or 4) rats were observed in the curative treatment group (group 5). CONCLUSIONS Treatment with DFSC after 4 h of sepsis induction downregulates tissue inflammatory responses by decreasing TNF-α levels and increasing Treg cell ratio. This also has a protective effect on intestinal tissues during sepsis.
Collapse
Affiliation(s)
- Leyla Topcu Sarica
- Department of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey
| | - Noushin Zibandeh
- Department of Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Deniz Genç
- Department of Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Fethi Gül
- Department of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey
| | - Tolga Akkoç
- TUBITAK MRC Genetic Engineering and Biotechnology Institute, Gebze, Turkey
| | - Erdem Faruk Kombak
- Department of Pathology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Leyla Cinel
- Department of Pathology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Tunç Akkoç
- Department of Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Ismail Cinel
- Department of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey.
| |
Collapse
|
|
31
|
Histone Deacetylation Inhibitors as Modulators of Regulatory T Cells. Int J Mol Sci 2020; 21:ijms21072356. [PMID: 32235291 PMCID: PMC7177531 DOI: 10.3390/ijms21072356] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/12/2020] [Accepted: 03/26/2020] [Indexed: 02/07/2023] Open
Abstract
Regulatory T cells (Tregs) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4+Forkhead box protein3+ (CD4+FOXP3+), these cells are a subset of CD4+ T lymphocytes and can originate from the thymus (tTregs) or from the periphery (pTregs). The malfunction of CD4+ Tregs is associated with autoimmune responses such as rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel diseases (IBD), psoriasis, systemic lupus erythematosus (SLE), and transplant rejection. Recent evidence supports an opposed role in sepsis. Therefore, maintaining functional Tregs is considered as a therapy regimen to prevent autoimmunity and allograft rejection, whereas blocking Treg differentiation might be favorable in sepsis patients. It has been shown that Tregs can be generated from conventional naïve T cells, called iTregs, due to their induced differentiation. Moreover, Tregs can be effectively expanded in vitro based on blood-derived tTregs. Taking into consideration that the suppressive role of Tregs has been mainly attributed to the expression and function of the transcription factor Foxp3, modulating its expression and binding to the promoter regions of target genes by altering the chromatin histone acetylation state may turn out beneficial. Hence, we discuss the role of histone deacetylation inhibitors as epigenetic modulators of Tregs in this review in detail.
Collapse
|
|
32
|
Mesenchymal Stem Cells Enhance Pulmonary Antimicrobial Immunity and Prevent Following Bacterial Infection. Stem Cells Int 2020; 2020:3169469. [PMID: 32300367 PMCID: PMC7142356 DOI: 10.1155/2020/3169469] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/18/2020] [Accepted: 03/02/2020] [Indexed: 12/21/2022] Open
Abstract
Background Immunosuppressants such as cyclophosphamide (CTX) have been employed to treat a wide array of autoimmune diseases. The most unfavourable side effects of these drugs are their suppression on the antimicrobial immunity and increasing the risk of infection. As a promising substitution/adjunct, mesenchymal stem cells (MSCs) are currently being tested in several clinical trials. However, their influence on the recipients' antimicrobial immunity remains unclear. Methods In this study, C57BL/6 mice were treated with either CTX or MSCs, and then both the innate and adaptive immunity of the lung were determined. To investigate the influence of CTX and MSCs on the immune defence against infection, the treated mice were intranasally infected with opportunistic pathogen Haemophilus influenzae (Hi). Bacterial clearance and antibacterial immune responses were analysed. Results Our data showed that CTX strongly inhibited the proliferation of lung immune cells, including alveolar macrophages (AMs) and T cells, whereas MSCs increased the numbers of these cells. CTX suppressed the phagocytic activity of AMs; on the contrary, MSCs enhanced it. Notably, infusion of MSCs led to a remarkable increase of regulatory T cells and Th1 cells in the lung. When infected by Hi, CTX did not significantly impair the elimination of invaded bacteria. However, MSC-treated mice exhibited accelerated bacterial clearance and moderate inflammation and tissue damage. Conclusion Our study reported that unlike traditional immunosuppressants, modulation of MSCs on the recipient's immune response is more elegant. It could preserve and even enhance the antimicrobial defence, suggesting that MSCs are better choice for patients with high risk of infection or those who need long-term immunosuppressive regimen.
Collapse
|
|
33
|
Wu KH, Cheng CC, Li JP, Weng TF, Yang SF, Pan HH, Chao YH. Toll-like receptor signalling associated with immunomodulation of umbilical cord-derived mesenchymal stem cells in mice with systemic lupus erythematosus. Lupus 2020; 29:165-175. [PMID: 31964222 DOI: 10.1177/0961203319898532] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
With potent immunomodulatory activities, mesenchymal stem cells (MSCs) have the potential to be a beneficial treatment option for diseases with aberrant immune responses such as systemic lupus erythematosus (SLE). However, the underlying mechanisms remain largely unknown. Here, we used NZBWF1 mice as a SLE animal model to examine immunomodulation of MSCs as well as to assess the role of Toll-like receptor signalling in this circumstance. We found that mice receiving MSCs had a significant decrease in severity of proteinuria at 20 and 22 weeks of age (p = 0.009 and p = 0.022, respectively). Serum anti-dsDNA levels were significantly lower compared with the control group (p = 0.016 and p = 0.036, respectively). C3 and C4 levels were significantly higher at 22 weeks of age (p = 0.046 and p = 0.016, respectively). Altered expression of inflammation-associated cytokine profiles in the serum was also noted in mice receiving MSCs. Down-regulation of myeloid differentiation factor 88 (MyD88)-nuclear factor-κB (NF-κB) signalling in the liver was demonstrated by quantitative polymerase chain reaction, ELISA and Western blotting. In addition to demonstrating the beneficial effects of MSC treatment in NZBWF1 mice, our study provided the first evidence for the association of MyD88-NF-κB signalling and MSC-mediated immunomodulation in this disease.
Collapse
Affiliation(s)
- K H Wu
- Division of Pediatric Hematology-Oncology, Children's Hospital, China Medical University, Taichung, Taiwan.,School of Post-baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan
| | - C C Cheng
- Laboratory Animal Service Center, Office of Research and Development, China Medical University, Taichung, Taiwan
| | - J P Li
- Rheumatology Research Center, China Medical University Hospital, Taichung, Taiwan.,School of Dentistry, National Defense Medical Center, Taipei, Taiwan
| | - T F Weng
- Division of Pediatric Hematology-Oncology, Children's Hospital, China Medical University, Taichung, Taiwan
| | - S F Yang
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.,Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - H H Pan
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Y H Chao
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| |
Collapse
|
|
34
|
Lopes-Pacheco M, Robba C, Rocco PRM, Pelosi P. Current understanding of the therapeutic benefits of mesenchymal stem cells in acute respiratory distress syndrome. Cell Biol Toxicol 2019; 36:83-102. [PMID: 31485828 PMCID: PMC7222160 DOI: 10.1007/s10565-019-09493-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 08/27/2019] [Indexed: 12/20/2022]
Abstract
The acute respiratory distress syndrome (ARDS) is a multifaceted lung disorder in which no specific therapeutic intervention is able to effectively improve clinical outcomes. Despite an improved understanding of molecular mechanisms and advances in supportive care strategies, ARDS remains associated with high mortality, and survivors usually face long-term morbidity. In recent years, preclinical studies have provided mounting evidence of the potential of mesenchymal stem cell (MSC)-based therapies in lung diseases and critical illnesses. In several models of ARDS, MSCs have been demonstrated to induce anti-inflammatory and anti-apoptotic effects, improve epithelial and endothelial cell recovery, and enhance microbial and alveolar fluid clearance, thus resulting in improved lung and distal organ function and survival. Early-stage clinical trials have also demonstrated the safety of MSC administration in patients with ARDS, but further, large-scale investigations are required to assess the safety and efficacy profile of these therapies. In this review, we summarize the main mechanisms whereby MSCs have been shown to exert therapeutic effects in experimental ARDS. We also highlight questions that need to be further elucidated and barriers that must be overcome in order to efficiently translate MSC research into clinical practice.
Collapse
Affiliation(s)
- Miquéias Lopes-Pacheco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Chiara Robba
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy
| | - Patricia Rieken Macêdo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. .,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.
| | - Paolo Pelosi
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy. .,Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy.
| |
Collapse
|
|
35
|
Khan RS, Newsome PN. A Comparison of Phenotypic and Functional Properties of Mesenchymal Stromal Cells and Multipotent Adult Progenitor Cells. Front Immunol 2019; 10:1952. [PMID: 31555259 PMCID: PMC6724467 DOI: 10.3389/fimmu.2019.01952] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 08/02/2019] [Indexed: 12/15/2022] Open
Abstract
Both Multipotent Adult Progenitor Cells and Mesenchymal Stromal Cells are bone-marrow derived, non-haematopoietic adherent cells, that are well-known for having immunomodulatory and pro-angiogenic properties, whilst being relatively non-immunogenic. However, they are phenotypically and functionally distinct cell types, which has implications for their efficacy in different settings. In this review we compare the phenotypic and functional properties of these two cell types, to help in determining which would be the superior cell type for different applications.
Collapse
Affiliation(s)
- Reenam S Khan
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Philip N Newsome
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| |
Collapse
|
|
36
|
Human Adipose Tissue-Derived Stromal Cells Attenuate the Multiple Organ Injuries Induced by Sepsis and Mechanical Ventilation in Mice. Inflammation 2019; 42:485-495. [PMID: 30317531 DOI: 10.1007/s10753-018-0905-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Mechanical ventilation (MV) can augment sepsis-induced organ injury. Previous studies indicate that human mesenchymal stem cells (hMSCs) have immune-modulatory effect. We hypothesize that human adipose tissue-derived stromal cells (hADSCs) could attenuate MV and sepsis-induced organ injury. Male C57BL/6 mice were randomized to five groups: Sham group; MV group; cecal ligation and puncture (CLP) group; CLP + MV group; and CLP + MV + hADSC group. Anesthetized mice were subjected to cecal ligation and puncture surgery. The mice then received mechanical ventilation (12 ml/kg), with or without the intervention of hADSCs. The survival rate, organ injury of the liver and kidney, total protein and cells in bronchoalveolar lavage fluid (BALF), and histological changes of the lung and liver were examined. The level of IL-6 in BALF was measured by ELISA. Real-time quantitative PCR was used to analyze mRNA of IL-6 and tumor necrosis factor-α (TNF-α). hADSC treatment increased survival rate of septic mice with MV. hADSCs attenuated dysfunction of the liver and kidney and decreased lung inflammation and tissue injury of the liver and lung. IL-6 level in BALF and TNF-α and IL-6 mRNA expression in the tissue of the lung, liver, and kidney were significantly reduced by hADSC treatment. MV with conventional tidal volume aggravates CLP-induced multiple organ injuries. hADSCs inhibited the compound injuries possibly through modulation of immune responses.
Collapse
|
|
37
|
Hoogduijn MJ, Lombardo E. Mesenchymal Stromal Cells Anno 2019: Dawn of the Therapeutic Era? Concise Review. Stem Cells Transl Med 2019; 8:1126-1134. [PMID: 31282113 PMCID: PMC6811696 DOI: 10.1002/sctm.19-0073] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 06/17/2019] [Indexed: 12/11/2022] Open
Abstract
2018 was the year of the first marketing authorization of an allogeneic stem cell therapy by the European Medicines Agency. The authorization concerns the use of allogeneic adipose tissue-derived mesenchymal stromal cells (MSCs) for treatment of complex perianal fistulas in Crohn's disease. This is a breakthrough in the field of MSC therapy. The last few years have, furthermore, seen some breakthroughs in the investigations into the mechanisms of action of MSC therapy. Although the therapeutic effects of MSCs have largely been attributed to their secretion of immunomodulatory and regenerative factors, it has now become clear that some of the effects are mediated through host phagocytic cells that clear administered MSCs and in the process adapt an immunoregulatory and regeneration supporting function. The increased interest in therapeutic use of MSCs and the ongoing elucidation of the mechanisms of action of MSCs are promising indicators that 2019 may be the dawn of the therapeutic era of MSCs and that there will be revived interest in research to more efficient, practical, and sustainable MSC-based therapies. Stem Cells Translational Medicine 2019;8:1126-1134.
Collapse
Affiliation(s)
- Martin J Hoogduijn
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | | |
Collapse
|
|
38
|
Laroye C, Boufenzer A, Jolly L, Cunat L, Alauzet C, Merlin JL, Yguel C, Bensoussan D, Reppel L, Gibot S. Bone marrow vs Wharton's jelly mesenchymal stem cells in experimental sepsis: a comparative study. Stem Cell Res Ther 2019; 10:192. [PMID: 31248453 PMCID: PMC6598309 DOI: 10.1186/s13287-019-1295-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/23/2019] [Accepted: 06/03/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The use of mesenchymal stem cells (MSCs) is being extensively studied in clinical trials in the setting of various diseases including diabetes, stroke, and progressive multiple sclerosis. The unique immunomodulatory properties of MSCs also point them as a possible therapeutic tool during sepsis and septic shock, a devastating syndrome associated with 30-35% mortality. However, MSCs are not equal regarding their activity, depending on their tissue origin. Here, we aimed at comparing the in vivo properties of MSCs according to their tissue source (bone marrow (BM) versus Wharton's jelly (WJ)) in a murine cecal ligation and puncture (CLP) model of sepsis that mimics a human peritonitis. We hypothesized that MSC properties may vary depending on their tissue source in the setting of sepsis. METHODS CLP, adult, male, C57BL/6 mice were randomized in 3 groups receiving respectively 0.25 × 106 BM-MSCs, 0.25 × 106 WJ-MSCs, or 150 μL phosphate-buffered saline (PBS) intravenously 24 h after the CLP procedure. RESULTS We observed that both types of MSCs regulated leukocyte trafficking and reduced organ dysfunction, while only WJ-MSCs were able to improve bacterial clearance and survival. CONCLUSION This study highlights the importance to determine the most appropriate source of MSCs for a given therapeutic indication and suggests a better profile for WJ-MSCs during sepsis.
Collapse
Affiliation(s)
- Caroline Laroye
- CHRU de Nancy, Unité de Thérapie Cellulaire et banque de Tissus, Allée du Morvan, 54500 Vandoeuvre-lès-Nancy, France
- INSERM UMRS-1116, Vandoeuvre-lès-Nancy, France
- CNRS, UMR 7365, 54500 Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
| | | | - Lucie Jolly
- INSERM UMRS-1116, Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
- INOTREM, 54500 Vandoeuvre-lès-Nancy, France
| | - Lisiane Cunat
- Université de Lorraine, 54000 Nancy, France
- EA 7300 Stress Immunité Pathogènes, 54500 vandoeuvre-lès-Nancy, France
| | - Corentine Alauzet
- Université de Lorraine, 54000 Nancy, France
- EA 7300 Stress Immunité Pathogènes, 54500 vandoeuvre-lès-Nancy, France
| | - Jean-Louis Merlin
- Université de Lorraine, 54000 Nancy, France
- Service de Biopathologie - Unité de Biologie des Tumeurs, Institut de Cancérologie de Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - Clémence Yguel
- CHRU de Nancy, laboratoire anatomie et cytologie pathologiques, 54500 Vandoeuvre-lès-Nancy, France
| | - Danièle Bensoussan
- CHRU de Nancy, Unité de Thérapie Cellulaire et banque de Tissus, Allée du Morvan, 54500 Vandoeuvre-lès-Nancy, France
- CNRS, UMR 7365, 54500 Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
| | - Loïc Reppel
- CHRU de Nancy, Unité de Thérapie Cellulaire et banque de Tissus, Allée du Morvan, 54500 Vandoeuvre-lès-Nancy, France
- CNRS, UMR 7365, 54500 Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
| | - Sébastien Gibot
- INSERM UMRS-1116, Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
- CHRU de Nancy, Service de Réanimation Médicale, Hôpital Central, 54000 Nancy, France
| |
Collapse
|
|
39
|
Grégoire C, Ritacco C, Hannon M, Seidel L, Delens L, Belle L, Dubois S, Vériter S, Lechanteur C, Briquet A, Servais S, Ehx G, Beguin Y, Baron F. Comparison of Mesenchymal Stromal Cells From Different Origins for the Treatment of Graft-vs.-Host-Disease in a Humanized Mouse Model. Front Immunol 2019; 10:619. [PMID: 31001253 PMCID: PMC6454068 DOI: 10.3389/fimmu.2019.00619] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 03/08/2019] [Indexed: 12/23/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have potent immunomodulatory properties that make them an attractive tool against graft- vs.-host disease (GVHD). However, despite promising results in phase I/II studies, bone marrow (BM-) derived MSCs failed to demonstrate their superiority over placebo in the sole phase III trial reported thus far. MSCs from different tissue origins display different characteristics, but their therapeutic benefits have never been directly compared in GVHD. Here, we compared the impact of BM-, umbilical cord (UC-), and adipose-tissue (AT-) derived MSCs on T-cell function in vitro and assessed their efficacy for the treatment of GVHD induced by injection of human peripheral blood mononuclear cells in NOD-scid IL-2Rγnull HLA-A2/HHD mice. In vitro, resting BM- and AT-MSCs were more potent than UC-MSCs to inhibit lymphocyte proliferation, whereas UC- and AT-MSCs induced a higher regulatory T-cell (CD4+CD25+FoxP3+)/T helper 17 ratio. Interestingly, AT-MSCs and UC-MSCs activated the coagulation pathway at a higher level than BM-MSCs. In vivo, AT-MSC infusions were complicated by sudden death in 4 of 16 animals, precluding an analysis of their efficacy. Intravenous MSC infusions (UC- or BM- combined) failed to significantly increase overall survival (OS) in an analysis combining data from 80 mice (hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.32–1.08, P = 0.087). In a sensitivity analysis we also compared OS in control vs. each MSC group separately. The results for the BM-MSC vs. control comparison was HR = 0.63 (95% CI 0.30–1.34, P = 0.24) while the figures for the UC-MSC vs. control comparison was HR = 0.56 (95% CI 0.28–1.10, P = 0.09). Altogether, these results suggest that MSCs from various origins have different effects on immune cells in vitro and in vivo. However, none significantly prevented death from GVHD. Finally, our data suggest that the safety profile of AT-MSC and UC-MSC need to be closely monitored given their pro-coagulant activities in vitro.
Collapse
Affiliation(s)
- Céline Grégoire
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, University Hospital Center of Liège, Liège, Belgium
| | - Caroline Ritacco
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Muriel Hannon
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Laurence Seidel
- Department of Biostatistics, SIMÉ, University Hospital Center of Liège, Liège, Belgium
| | - Loïc Delens
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Ludovic Belle
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Sophie Dubois
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Sophie Vériter
- Endocrine Cell Therapy, Centre of Tissue and Cellular Therapy, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Chantal Lechanteur
- Laboratory of Cell and Gene Therapy, University Hospital Center and University of Liège, Liège, Belgium
| | - Alexandra Briquet
- Laboratory of Cell and Gene Therapy, University Hospital Center and University of Liège, Liège, Belgium
| | - Sophie Servais
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, University Hospital Center of Liège, Liège, Belgium
| | - Gregory Ehx
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Yves Beguin
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, University Hospital Center of Liège, Liège, Belgium.,Laboratory of Cell and Gene Therapy, University Hospital Center and University of Liège, Liège, Belgium
| | - Frédéric Baron
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, University Hospital Center of Liège, Liège, Belgium
| |
Collapse
|
|
40
|
Beljanski V, Grinnemo KH, Österholm C. Pleiotropic roles of autophagy in stem cell-based therapies. Cytotherapy 2019; 21:380-392. [PMID: 30876741 DOI: 10.1016/j.jcyt.2019.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/25/2019] [Accepted: 02/19/2019] [Indexed: 02/07/2023]
Abstract
Stem cells (SCs) have been proven to possess regenerative and immunomodulatory properties and can be used to treat diseases that involve loss of cells due to tissue damage or inflammation. For this approach to succeed, SCs or their derivatives should be able to engraft in the target tissue at least for a short period of time. Unfortunately, once injected, therapeutic SCs will encounter a hostile environment, including hypoxia, lack of nutrients and stromal support, and cells may also be targeted and rejected by the immune system. Therefore, SC's stress-response mechanisms likely play a significant role in survival of injected cells and possibly contribute to their therapeutic efficacy. Autphagy, a stress-response pathway, is involved in many different cellular processes, such as survival during hypoxia and nutrient deprivation, cellular differentiation and de-differentiation, and it can also contribute to their immunovisibility by regulating antigen presentation and cytokine secretion. Autophagy machinery interacts with many proteins and signaling pathways that regulate SC properties, including PI3K/Akt, mammalian target of rapamycin (mTOR), Wnt, Hedgehog and Notch, and it is also involved in regulating intracellular reactive oxygen species (ROS) levels. In this review, we contend that autophagy is an important therapeutic target that can be used to improve the outcome of SC-based tissue repair and regeneration. Further research should reveal whether inhibition or stimulation of autophagy increases the therapeutic utility of SCs and it should also identify appropriate therapeutic regimens that can be applied in the clinic.
Collapse
Affiliation(s)
- Vladimir Beljanski
- NSU Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, Florida, USA.
| | - Karl-Henrik Grinnemo
- Department of Molecular Medicine and Surgery, Division of Cardiothoracic Surgery and Anesthesiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Surgical Sciences, Division of Cardiothoracic Surgery and Anesthesiology, Uppsala University, Akademiska University Hospital, Uppsala, Sweden
| | - Cecilia Österholm
- Department of Molecular Medicine and Surgery, Division of Cardiothoracic Surgery and Anesthesiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
41
|
Erpicum P, Weekers L, Detry O, Bonvoisin C, Delbouille MH, Grégoire C, Baudoux E, Briquet A, Lechanteur C, Maggipinto G, Somja J, Pottel H, Baron F, Jouret F, Beguin Y. Infusion of third-party mesenchymal stromal cells after kidney transplantation: a phase I-II, open-label, clinical study. Kidney Int 2019; 95:693-707. [DOI: 10.1016/j.kint.2018.08.046] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 07/25/2018] [Accepted: 08/23/2018] [Indexed: 02/08/2023]
|
|
42
|
Marrazzo P, Crupi AN, Alviano F, Teodori L, Bonsi L. Exploring the roles of MSCs in infections: focus on bacterial diseases. J Mol Med (Berl) 2019; 97:437-450. [PMID: 30729280 DOI: 10.1007/s00109-019-01752-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 02/08/2023]
Abstract
Despite human healthcare advances, some microorganisms continuously react evolving new survival strategies, choosing between a commensal fitness and a pathogenic attitude. Many opportunistic microbes are becoming an increasing cause of clinically evident infections while several renowned infectious diseases sustain a considerable number of deaths. Besides the primary and extensively investigated role of immune cells, other cell types are involved in the microbe-host interaction during infection. Interestingly, mesenchymal stem cells (MSCs), the current leading players in cell therapy approaches, have been suggested to contribute to tackling pathogens and modulating the host immune response. In this context, this review critically explores MSCs' role in E. coli, S. aureus, and polymicrobial infections. Summarizing from various studies, in vitro and in vivo results support the mechanistic involvement of MSCs and their derivatives in fighting infection and in contributing to microbial spreading. Our work outlines the double face of MSCs during infection, disease, and sepsis, highlighting potential pitfalls in MSC-based therapy due to the MSCs' susceptibility to pathogens' weapons. We also identify potential targets to improve infection treatments, and propose the potential applications of MSCs for vaccine research.
Collapse
Affiliation(s)
- Pasquale Marrazzo
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, Italy
| | | | - Francesco Alviano
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, Italy.
| | - Laura Teodori
- Diagnostics and Metrology, FSN-TECFIS-DIM, Enea Frascati, Rome, Italy
| | - Laura Bonsi
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, Italy
| |
Collapse
|
|
43
|
Liang X, Li T, Zhou Q, Pi S, Li Y, Chen X, Weng Z, Li H, Zhao Y, Wang H, Chen Y. Mesenchymal stem cells attenuate sepsis-induced liver injury via inhibiting M1 polarization of Kupffer cells. Mol Cell Biochem 2019; 452:187-197. [PMID: 30178273 DOI: 10.1007/s11010-018-3424-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Accepted: 08/10/2018] [Indexed: 02/05/2023]
Abstract
Sepsis is a leading cause of death in intensive care units that can result in acute hepatic damage. Animal experiments and clinical trials have shown that mesenchymal stem cell (MSC) therapy has some beneficial in several liver diseases. However, the protective effects of MSC therapy on sepsis-induced hepatic damage and associated mechanisms are not completely understood. The aim of the present study was to investigate the effects of MSCs on sepsis-induced liver injury and underlying mechanisms. A rat model of sepsis-induced liver injury was established by cecal ligation and puncture, and serum alanine aminotransferase and aspartate transaminase activities as well as liver histological changes were measured. Inflammatory cytokines, Kupffer cell M1 phenotype markers, and associated signal molecules were also determined in septic rats and in lipopolysaccharide (LPS)-treated Kupffer cells. Our results showed that injection of MSCs attenuated sepsis-induced liver injury. Treatment with MSCs inhibited activation of Kupffer cells towards M1 phenotype, attenuated TNF-α and IL-6 expression, and promoted IL-4 and IL-10 expression in septic rats and LPS-treated Kupffer cells. Furthermore, MSCs also inhibited the nuclear translocation of nuclear factor-kappa B in LPS-challenged Kupffer cells and the liver of septic rats. These results indicated that MSCs attenuated sepsis-induced liver injury through suppressing M1 polarization of Kupffer cells.
Collapse
Affiliation(s)
- Xujing Liang
- Department of Infectious Disease, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China
| | - Taoyuan Li
- Department of Infectious Disease, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China
| | - Qiuchan Zhou
- Institute of Laboratory Animal Science, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China
| | - Sainan Pi
- Department of Infectious Disease, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China
| | - Yadan Li
- Institute of Biomedicine, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China
| | - Xiaojia Chen
- Institute of Biomedicine, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China
| | - Zeping Weng
- Department of Pathology, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China
| | - Hongmei Li
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China
| | - Ying Zhao
- Institute of Biomedicine, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China
| | - Huadong Wang
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China.
| | - Youpeng Chen
- Department of Infectious Disease, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China.
| |
Collapse
|
|
44
|
Zhou Y, Zhang Y, Johnson A, Venable A, Griswold J, Pappas D. Combined CD25, CD64, and CD69 biomarker panel for flow cytometry diagnosis of sepsis. Talanta 2019; 191:216-221. [DOI: 10.1016/j.talanta.2018.08.058] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 08/21/2018] [Accepted: 08/23/2018] [Indexed: 01/04/2023]
|
|
45
|
Horie S, Gonzalez HE, Laffey JG, Masterson CH. Cell therapy in acute respiratory distress syndrome. J Thorac Dis 2018; 10:5607-5620. [PMID: 30416812 DOI: 10.21037/jtd.2018.08.28] [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] [Indexed: 02/06/2023]
Abstract
Acute respiratory distress syndrome (ARDS) is driven by a severe pro-inflammatory response resulting in lung damage, impaired gas exchange and severe respiratory failure. There is no specific treatment that effectively improves outcome in ARDS. However, in recent years, cell therapy has shown great promise in preclinical ARDS studies. A wide range of cells have been identified as potential candidates for use, among these are mesenchymal stromal cells (MSCs), which are adult multi-lineage cells that can modulate the immune response and enhance repair of damaged tissue. The therapeutic potential of MSC therapy for sepsis and ARDS has been demonstrated in multiple in vivo models. The therapeutic effect of these cells seems to be due to two different mechanisms; direct cellular interaction, and paracrine release of different soluble products such as extracellular vesicles (EVs)/exosomes. Different approaches have also been studied to enhance the therapeutic effect of these cells, such as the over-expression of anti-inflammatory or pro-reparative molecules. Several clinical trials (phase I and II) have already shown safety of MSCs in ARDS and other diseases. However, several translational issues still need to be addressed, such as the large-scale production of cells, and their potentiality and variability, before the therapeutic potential of stem cells therapies can be realized.
Collapse
Affiliation(s)
- Shahd Horie
- Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland
| | - Hector Esteban Gonzalez
- Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland
| | - John G Laffey
- Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland.,Department of Anesthesia and Intensive Care Medicine, Galway University Hospitals, SAOLTA Hospital Group, Ireland
| | - Claire H Masterson
- Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland
| |
Collapse
|
|
46
|
Laroye C, Lemarié J, Boufenzer A, Labroca P, Cunat L, Alauzet C, Groubatch F, Cailac C, Jolly L, Bensoussan D, Reppel L, Gibot S. Clinical-grade mesenchymal stem cells derived from umbilical cord improve septic shock in pigs. Intensive Care Med Exp 2018; 6:24. [PMID: 30091119 PMCID: PMC6082751 DOI: 10.1186/s40635-018-0194-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 07/30/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Septic shock is the leading cause of death in intensive care units. The pathophysiological complexity of this syndrome contributes to an absence of specific treatment. Several preclinical studies in murine models of septic shock have shown improvements to organ injury and survival after administration of mesenchymal stem cells (MSCs). To better mimic a clinical approach in humans, we investigated the impact of randomized controlled double-blind administration of clinical-grade umbilical cord-derived MSCs to a relevant pig model of septic shock. METHODS Septic shock was induced by fecal peritonitis in 12 male domestic pigs. Animals were resuscitated by an experienced intensivist including fluid administration and vasopressors. Four hours after the induction of peritonitis, pigs were randomized to receive intravenous injection of thawed umbilical cord-derived MSCs (UCMSC) (1 × 106 UCMSCs/kg diluted in 75 mL hydroxyethyl starch (HES), (n = 6) or placebo (HES alone, n = 6). Researchers were double-blinded to the treatment administered. Hemodynamic parameters were continuously recorded. Gas exchange, acid-base status, organ function, and plasma cytokine concentrations were assessed at regular intervals until 24 h after the onset of peritonitis when animals were sacrificed under anesthesia. RESULTS Peritonitis induced profound hypotension, hyperlactatemia, and multiple organ failure. These disorders were significantly attenuated when animals were treated with UCMSCs. In particular, cardiovascular failure was attenuated, as attested by a better mean arterial pressure and reduced lactatemia, despite lower norepinephrine requirements. As such, UCMSCs improved survival in this very severe model (60% survival vs. 0% at 24 h). CONCLUSION UCMSCs administration is beneficial in this pig model of polymicrobial septic shock.
Collapse
Affiliation(s)
- Caroline Laroye
- CHRU de Nancy, Unité de Thérapie Cellulaire et banque de tissus, 54500 Vandoeuvre-lès-Nancy, France
- INSERM, U1116, 54500 Vandoeuvre-lès-Nancy, France
- CNRS, UMR 7365, 54500 Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
| | - Jérémie Lemarié
- INSERM, U1116, 54500 Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
- CHRU de Nancy, Service de Réanimation Médicale, Hôpital Central, 54000 Nancy, France
| | | | - Pierre Labroca
- CHRU de Nancy, Service de Réanimation Médicale, Hôpital Central, 54000 Nancy, France
| | - Lisiane Cunat
- Université de Lorraine, 54000 Nancy, France
- EA 7300 Stress Immunité Pathogènes, 54500 Vandoeuvre-lès-Nancy, France
| | - Corentine Alauzet
- Université de Lorraine, 54000 Nancy, France
- EA 7300 Stress Immunité Pathogènes, 54500 Vandoeuvre-lès-Nancy, France
| | - Frédérique Groubatch
- Université de Lorraine, 54000 Nancy, France
- Ecole de chirurgie, 54500 Vandoeuvre-lès-Nancy, France
| | - Clémence Cailac
- CHRU de Nancy, laboratoire anatomie et cytologie pathologiques, 54000 Nancy, France
| | - Lucie Jolly
- INSERM, U1116, 54500 Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
- INOTREM, 54500 Vandoeuvre-lès-Nancy, France
| | - Danièle Bensoussan
- CHRU de Nancy, Unité de Thérapie Cellulaire et banque de tissus, 54500 Vandoeuvre-lès-Nancy, France
- CNRS, UMR 7365, 54500 Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
| | - Loïc Reppel
- CHRU de Nancy, Unité de Thérapie Cellulaire et banque de tissus, 54500 Vandoeuvre-lès-Nancy, France
- CNRS, UMR 7365, 54500 Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
| | - Sébastien Gibot
- INSERM, U1116, 54500 Vandoeuvre-lès-Nancy, France
- Université de Lorraine, 54000 Nancy, France
- CHRU de Nancy, Service de Réanimation Médicale, Hôpital Central, 54000 Nancy, France
| |
Collapse
|
|
47
|
Alfaifi M, Eom YW, Newsome PN, Baik SK. Mesenchymal stromal cell therapy for liver diseases. J Hepatol 2018; 68:1272-1285. [PMID: 29425678 DOI: 10.1016/j.jhep.2018.01.030] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 01/16/2018] [Accepted: 01/30/2018] [Indexed: 02/08/2023]
Abstract
The therapeutic potential of mesenchymal stromal cells (MSCs) in the treatment of liver fibrosis is predominantly based on their immunosuppressive properties, and their ability to secrete various trophic factors. This potential has been investigated in clinical and preclinical studies. Although the therapeutic mechanisms of MSC transplantation are still not fully characterised, accumulating evidence has revealed that various trophic factors secreted by MSCs play key therapeutic roles in regeneration by alleviating inflammation, apoptosis, and fibrosis as well as stimulating angiogenesis and tissue regeneration in damaged liver. In this review, we summarise the safety, efficacy, potential transplantation routes and therapeutic effects of MSCs in patients with liver fibrosis. We also discuss some of the key strategies to enhance the functionality of MSCs, which include sorting and/or priming with factors such as cytokines, as well as genetic engineering.
Collapse
Affiliation(s)
- Mohammed Alfaifi
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Young Woo Eom
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, South Korea; Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea
| | - Philip N Newsome
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK; National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
| | - Soon Koo Baik
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, South Korea; Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea.
| |
Collapse
|
|
48
|
Andreeva ER, Buravkova LB. The Role of Interplay of Mesenchymal Stromal Cells and Macrophages in Physiological and Reparative Tissue Remodeling. ACTA ACUST UNITED AC 2018. [DOI: 10.1134/s0362119718010036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
|
|
49
|
Abstract
Abstract
Sepsis is a life-threatening syndrome resulting in shock and organ dysfunction stemming from a microbial infection. Sepsis has a mortality of 40% and is implicated in half of all in-hospital deaths. The host immune response to microbial infection is critical, with early-phase sepsis characterized by a hyperinflammatory immune response, whereas the later phase of sepsis is often complicated by suppression. Sepsis has no treatment, and management remains supportive.
Stem cells constitute exciting potential therapeutic agents for sepsis. In this review, we examine the rationale for stem cells in sepsis, focusing on mesenchymal stem/stromal cells, which currently demonstrate the greatest therapeutic promise. We examine the preclinical evidence base and evaluate potential mechanisms of action of these cells that are important in the setting of sepsis. We discuss early-phase clinical trials and critically appraise translational barriers to the use of mesenchymal stem/stromal cells in patients with sepsis.
Collapse
|
|
50
|
Tang BL. The use of mesenchymal stem cells (MSCs) for amyotrophic lateral sclerosis (ALS) therapy – a perspective on cell biological mechanisms. Rev Neurosci 2017; 28:725-738. [DOI: 10.1515/revneuro-2017-0018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 04/04/2017] [Indexed: 12/12/2022]
Abstract
AbstractRecent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner. Novel ways whereby MSCs could act in modifying disease progression should also be explored. In this review, I discuss the known, emerging and postulated mechanisms of action underlying effects that transplanted MSCs may exert to promote motor neuron survival and/or to encourage regeneration in ALS. I shall also speculate on how transplanted cells may alter the diseased environment so as to minimize non-neuron cell autonomous damages by immune cells and astrocytes.
Collapse
Affiliation(s)
- Bor Luen Tang
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Medical Drive, Singapore 117597, Singapore
| |
Collapse
|