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Yuan Y, Liu T. Influence of mesenchymal stem cells from different origins on the therapeutic effectiveness of systemic lupus erythematosus. Exp Cell Res 2024; 442:114263. [PMID: 39307406 DOI: 10.1016/j.yexcr.2024.114263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/09/2024] [Accepted: 09/19/2024] [Indexed: 11/01/2024]
Abstract
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disorder characterized by alterations in the balance between inflammatory and regulatory cytokines. Mesenchymal stem cells (MSCs), which are non-hematopoietic stem cells with multipotent differentiation potential, due to their immunomodulatory, tissue repair, low immunogenicity, and chemotactic properties, have garnered increasing interest in SLE treatment. Studies increasingly reveal the heterogeneous nature of MSC populations. With sources including dental pulp, adipose tissue, bone marrow, and umbilical cord, the therapeutic effects of MSCs on SLE vary depending on their origin. This review consolidates clinical research on MSCs from different sources in treating SLE and analyzes the possible causes underlying these variable outcomes. Additionally, it elucidates five potential factors impacting the outcomes of MSC therapy in SLE: the influence of the microenvironment on MSCs, the complexity and paradoxical aspects of MSC mechanisms in SLE treatment, the heterogeneity of MSCs, the in vivo differentiation potential and post-transplant survival rates of MSCs, and disparities in MSC preparation conditions.
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Affiliation(s)
- Yuan Yuan
- Hengyang Medical College, University of South China, Hengyang, 421001, Hunan Province, China.
| | - Tong Liu
- Hengyang Medical College, University of South China, Hengyang, 421001, Hunan Province, China
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2
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Neo SH, Her Z, Othman R, Tee CA, Ong LC, Wang Y, Tan I, Tan J, Yang Y, Yang Z, Chen Q, Boyer LA. Expansion of human bone marrow-derived mesenchymal stromal cells with enhanced immunomodulatory properties. Stem Cell Res Ther 2023; 14:259. [PMID: 37726837 PMCID: PMC10510228 DOI: 10.1186/s13287-023-03481-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 08/29/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) have broad potential as a cell therapy including for the treatment of drug-resistant inflammatory conditions with abnormal T cell proliferation such as graft-versus-host disease (GVHD). Clinical success, however, has been complicated by the heterogeneity of culture-expanded MSCs as well as donor variability. Here, we devise culture conditions that promote expansion of MSCs with enhanced immunomodulatory functions both in vitro and in animal models of GVHD. METHODS Human bone marrow-derived MSCs were expanded at high-confluency (MSCHC) and low-confluency state (MSCLC). Their immunomodulatory properties were evaluated with in vitro co-culture assays based on suppression of activated T cell proliferation and secretion of pro-inflammatory cytokines from activated T cells. Metabolic state of these cells was determined, while RNA sequencing was performed to explore transcriptome of these MSCs. Ex vivo expanded MSCHC or MSCLC was injected into human peripheral blood mononuclear cells (PBMC)-induced GVHD mouse model to determine their in vivo therapeutic efficacy based on clinical grade scoring, human CD45+ blood count and histopathological examination. RESULTS As compared to MSCLC, MSCHC significantly reduced both the proliferation of anti-CD3/CD28-activated T cells and secretion of pro-inflammatory cytokines upon MSCHC co-culture across several donors even in the absence of cytokine priming. Mechanistically, metabolic analysis of MSCHC prior to co-culture with activated T cells showed increased glycolytic metabolism and lactate secretion compared to MSCLC, consistent with their ability to inhibit T cell proliferation. Transcriptome analysis further revealed differential expression of immunomodulatory genes including TRIM29, BPIFB4, MMP3 and SPP1 in MSCHC as well as enriched pathways including cytokine-cytokine receptor interactions, cell adhesion and PI3K-AKT signalling. Lastly, we demonstrate in a human PBMC-induced GVHD mouse model that delivery of MSCHC showed greater suppression of inflammation and improved outcomes compared to MSCLC and saline controls. CONCLUSION Our study provides evidence that ex vivo expansion of MSCs at high confluency alters the metabolic and transcriptomic states of these cells. Importantly, this approach maximizes the production of MSCs with enhanced immunomodulatory functions without priming, thus providing a non-invasive and generalizable strategy for improving the use of MSCs for the treatment of inflammatory diseases.
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Affiliation(s)
- Shu Hui Neo
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
| | - Zhisheng Her
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
- Invivocue Pte Ltd, 51 Science Park Road, #01-11/13 The Aries, Singapore Science Park II, Singapore, 117586, Republic of Singapore
| | - Rashidah Othman
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
| | - Ching Ann Tee
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
| | - Li Ching Ong
- Invivocue Pte Ltd, 51 Science Park Road, #01-11/13 The Aries, Singapore Science Park II, Singapore, 117586, Republic of Singapore
| | - Yuehua Wang
- Invivocue Pte Ltd, 51 Science Park Road, #01-11/13 The Aries, Singapore Science Park II, Singapore, 117586, Republic of Singapore
| | - Irwin Tan
- Invivocue Pte Ltd, 51 Science Park Road, #01-11/13 The Aries, Singapore Science Park II, Singapore, 117586, Republic of Singapore
| | - Jaylen Tan
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
| | - Yanmeng Yang
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
| | - Zheng Yang
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore
- Department of Orthopaedic Surgery, National University of Singapore, NUHS, 1E Kent Ridge RoadTower Block 11, Singapore, 119288, Republic of Singapore
- NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, 27 Medical Drive, DSO (Kent Ridge) Building, Level 4, Singapore, 117510, Republic of Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore.
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore, 117545, Republic of Singapore.
| | - Laurie A Boyer
- Critical Analytics for Manufacturing of Personalized Medicine (CAMP), Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Enterprise Wing, #04-13/14, Singapore, 138602, Republic of Singapore.
- Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
- Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
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Riekert M, Almanzar G, Schmalzing M, Schütze N, Jakob F, Prelog M. Mesenchymal stem cells modulate IL-17 and IL-9 production induced by Th17-inducing cytokine conditions in autoimmune arthritis: an explorative analysis. Adv Rheumatol 2023; 63:37. [PMID: 37525265 DOI: 10.1186/s42358-023-00317-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 07/19/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND The importance of proinflammatory T-cells and their cytokine production in patients with autoimmune arthritis has been widely described. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have come into focus as a potential therapeutic concept. The aim of this study was to investigate the influence of MSCs on the phenotype, cytokine profile, and functionality of naive and non-naive CD4+ T-cells from healthy donors (HD) and patients with autoimmune arthritis under Th17-cytokine polarizing conditions in an explorative way using a transwell system prohibiting any cell-cell-contact. METHODS Magnetically isolated naive and non-naive CD4+ T-cells were stimulated under Th17-polarizing proinflammatory cytokine conditions in presence and absence of bone marrow derived mesenchymal stromal cells (MSCs). After an incubation period of 6 days, the proportions of the T-cell subpopulations TEMRA (CD45RA+CD27-), memory (CD45RA-CD27+), effector (CD45RA-CD27-) and naive cells (CD45RA+CD27+) were determined. Quantitative immunofluorescence intensity was used as a measure for IL-9, IL-17 and IFN-γ production in each subpopulation. RESULTS In isolated naive CD4+ T-cells from HD and patients, MSCs suppressed the differentiation of naive towards an effector phenotype while memory and naive cells showed higher percentages in culture with MSCs. In patients, MSCs significantly decreased the proportion of IL-9 and IL-17 producing effector T-cells. MSCs also reduced IFN-γ production in the naive and memory phenotype from HD. CONCLUSION The results of the study indicate significant immunomodulatory properties of MSCs, as under Th17-polarizing conditions MSCs are still able to control T-cell differentiation and proinflammatory cytokine production in both HD and patients with autoimmune arthritis.
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Affiliation(s)
- Maximilian Riekert
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany.
- Department of Oral and Craniomaxillofacial and Plastic Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Straße 62, 50924, Cologne, Germany.
| | - Giovanni Almanzar
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Marc Schmalzing
- Department of Internal Medicine II, University Hospital of Wuerzburg, Wuerzburg, Germany
| | - Norbert Schütze
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany
| | - Franz Jakob
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany
| | - Martina Prelog
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany
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Yazdani A, Bahrami F, Pourgholaminejad A, Moghadasali R. A biological and a mathematical model of SLE treated by mesenchymal stem cells covering all the stages of the disease. Theory Biosci 2023; 142:167-179. [PMID: 37071370 DOI: 10.1007/s12064-023-00390-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 03/10/2023] [Indexed: 04/19/2023]
Abstract
In this study, we proposed a biological model explaining the progress of autoimmune activation along different stages of systemic lupus erythematosus (SLE). For any upcoming stage of SLE, any new component is introduced, when it is added to the model. Particularly, the interaction of mesenchymal stem cells, with the components of the model, is specified in a way that both the inflammatory and anti-inflammatory functions of these cells would be covered. The biological model is then recapitulated to a model with less complexity that explains the main features of the problem. Later, a 7th-order mathematical model for SLE is proposed, based on this simplified model. Finally, the range of validity of the proposed mathematical model was assessed. For this purpose, we simulated the model and analyzed the simulation results in case of some known behaviors of the disease, such as tolerance breach, the appearance of systemic inflammation, development of clinical signs, and occurrence of flares and improvements. The model was able to reproduce these events, qualitatively.
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Affiliation(s)
- Ali Yazdani
- Human Motor Control and Computational Neuroscience Lab, School of Electrical and Computer Engineering, College of Engineering, University of Tehran, Tehran, Iran
| | - Fariba Bahrami
- Human Motor Control and Computational Neuroscience Lab, School of Electrical and Computer Engineering, College of Engineering, University of Tehran, Tehran, Iran.
| | - Arash Pourgholaminejad
- Department of Immunology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Reza Moghadasali
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Hu W, Wang W, Jiang X, Wang Z, Lin R. Mesenchymal stem cells can prevent or promote the progression of colon cancer based on their timing of administration. J Transl Med 2023; 21:227. [PMID: 36978120 PMCID: PMC10045613 DOI: 10.1186/s12967-023-04028-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/28/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC) therapy has been shown to have some therapeutic effects in rodent models and patients with IBD; however, its role in colon tumor models is controversial. In this study, the potential role and mechanisms of bone marrow-derived MSCs (BM-MSCs) in colitis-associated colon cancer (CAC) were investigated. METHODS The CAC mouse model was established with azoxymethane (AOM) and dextran sulfate sodium (DSS). The mice were administered an intraperitoneal injection of MSCs once weekly for different periods. The progression of CAC and the cytokine expression in tissues was assessed. Immunofluorescence staining was used to detect MSCs localization. Levels of immune cells in the spleen and lamina propria of the colon were detected using flow cytometry. A co-culture of MSCs and naïve T cells was performed to determine the effect of MSCs on naïve T cell differentiation. RESULTS Early administration of MSCs inhibited the occurrence of CAC, while late administration promoted the progression of CAC. The inhibitory effect of early injection in mice was characterized by the expression of inflammatory cytokines in colon tissue was decreased, and induction of T regulatory cells (Tregs) infiltration via TGF-β. The promotive effect of late injection was characterized by a shift of T helper (Th) 1/Th2 immune balance toward a Th2 phenotype through IL-4 secretion. IL-12 can reverse this shift to Th2 accumulation in mice. CONCLUSION MSCs can curb the progression of colon cancer by inducing Treg accumulation via TGF-β at the early stage of inflammatory transformation but promote the progression of colon cancer by inducing a shift in Th1/Th2 immune balance to Th2 through IL-4 secretion at the late stage. And the immune balance of Th1/Th2 influenced by MSCs could be reversed by IL-12.
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Affiliation(s)
- Weiqian Hu
- Department of Digestive, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Weijun Wang
- Department of Digestive, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xin Jiang
- Department of Digestive, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zeyu Wang
- Department of Digestive, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Rong Lin
- Department of Digestive, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Dysregulated balance in Th17/Treg axis of Pristane-induced lupus mouse model, are mesenchymal stem cells therapeutic? Int Immunopharmacol 2023; 117:109699. [PMID: 36867923 DOI: 10.1016/j.intimp.2023.109699] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/20/2022] [Accepted: 01/04/2023] [Indexed: 03/05/2023]
Abstract
BACKGROUND Despite advances in general and targeted immunosuppressive therapies, limiting all mainstay treatment options in refractory systemic lupus erythematosus (SLE) cases has necessitated the development of new therapeutic strategies. Mesenchymal stem cells (MSCs) have recently emerged with unique properties, including a solid propensity to reduce inflammation, exert immunomodulatory effects, and repair injured tissues. METHODS An animal model of acquired SLE mice was induced via intraperitoneal immunization with Pristane and affirmed by measuring specific biomarkers. Bone marrow (BM) MSCs were isolated from healthy BALB/c mice and cultured in vitro, then were identified and confirmed by flow cytometry and cytodifferentiation. Systemic MSCs transplantation was performed and then several parameters were analyzed and compared, including specific cytokines (IL-17, IL-4, IFN-ɣ, TGF-β) at the serum level, the percentage of Th cell subsets (Treg/Th17, Th1/Th2) in splenocytes, and also the relief of lupus nephritis, respectively by enzyme-linked immunosorbent assay (ELISA), flow cytometry analysis and by hematoxylin & eosin staining and also immunofluorescence assessment. Experiments were carried out with different initiation treatment time points (early and late stages of disease). Analysis of variance (ANOVA) followed by post hoc Tukey's test was used for multiple comparisons. RESULTS The rate of proteinuria, anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies, and serum creatinine levels decreased with BM-MSCs transplantation. These results were associated with attenuated lupus renal pathology in terms of reducing IgG and C3 deposition and lymphocyte infiltration. Our findings suggested that TGF-β (associated with lupus microenvironment) can contribute to MSC-based immunotherapy by modulating the population of TCD4+ cell subsets. Obtained results indicated that MSCs-based cytotherapy could negatively affect the progression of induced SLE by recovering the function of Treg cells, suppressing Th1, Th2, and Th17 lymphocyte function, and downregulating their pro-inflammatory cytokines. CONCLUSION MSC-based immunotherapy showed a delayed effect on the progression of acquired SLE in a lupus microenvironment-dependent manner. Allogenic MSCs transplantation revealed the ability to re-establish the balance of Th17/Treg, Th1/Th2 and restore the plasma cytokines network in a pattern dependent on disease conditions. The conflicting results of early versus advanced therapy suggest that MSCs may produce different effects depending on when they are administered and their activation status.
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Večerić-Haler Ž, Sever M, Kojc N, Halloran PF, Boštjančič E, Mlinšek G, Oblak M, Poženel P, Švajger U, Hartman K, Kneževič M, Barlič A, Girandon L, Aleš Rigler A, Zver S, Buturović Ponikvar J, Arnol M. Autologous Mesenchymal Stem Cells for Treatment of Chronic Active Antibody-Mediated Kidney Graft Rejection: Report of the Phase I/II Clinical Trial Case Series. Transpl Int 2022; 35:10772. [PMID: 36484064 PMCID: PMC9722440 DOI: 10.3389/ti.2022.10772] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 11/08/2022] [Indexed: 11/23/2022]
Abstract
Mesenchymal stem cell (MSCs) therapy has already been studied in kidney transplant recipients (KTRs), and the available data showed that it is safe and well tolerated. The aim of this study was to evaluate the safety and efficacy of autologous MSCs in combination with standard therapy in KTRs with biopsy-proven chronic active antibody-mediated rejection (AMR). Patients with biopsy-proven chronic active AMR received treatment with autologous bone marrow-derived MSCs (3 × 106 cells/kg iv) after completion of standard therapy and were followed for up to 12 months. The primary endpoints were safety by assessment of adverse events. Secondary endpoints included assessment of kidney graft function, immunological and histological changes related to AMR activity and chronicity assessed by conventional microscopy and molecular transcripts. A total of 3 patients were enrolled in the study before it was terminated prematurely because of adverse events. We found that AMR did not improve in any of the patients after treatment with MSCs. In addition, serious adverse events were observed in one case when autologous MSCs therapy was administered in the late phase after kidney transplantation, which requires further elucidation.
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Affiliation(s)
- Željka Večerić-Haler
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,*Correspondence: Željka Večerić-Haler,
| | - Matjaž Sever
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,Department of Haematology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Nika Kojc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Philip F. Halloran
- Division of Nephrology and Transplant Immunology, Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, AB, Canada
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Gregor Mlinšek
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Manca Oblak
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Primož Poženel
- Division for Cells and Tissue, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
| | - Urban Švajger
- Division for Cells and Tissue, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
| | - Katrina Hartman
- Division for Cells and Tissue, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
| | | | - Ariana Barlič
- Educell d.o.o Cell Therapy Service, Ljubljana, Slovenia
| | | | - Andreja Aleš Rigler
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Samo Zver
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,Department of Haematology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Jadranka Buturović Ponikvar
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Miha Arnol
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Kamen DL, Wallace C, Li Z, Wyatt M, Paulos C, Wei C, Wang H, Wolf BJ, Nietert PJ, Gilkeson G. Safety, immunological effects and clinical response in a phase I trial of umbilical cord mesenchymal stromal cells in patients with treatment refractory SLE. Lupus Sci Med 2022; 9:e000704. [PMID: 35820718 PMCID: PMC9277402 DOI: 10.1136/lupus-2022-000704] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/23/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Reports of clinical improvement following mesenchymal stromal cell (MSC) infusions in refractory lupus patients at a single centre in China led us to perform an explorative phase I trial of umbilical cord derived MSCs in patients refractory to 6 months of immunosuppressive therapy. METHODS Six women with a SLEDAI >6, having failed standard of care therapy, received one intravenous infusion of 1×106 MSCs/kg of body weight. They maintained their current immunosuppressives, but their physician was allowed to adjust corticosteroids initially for symptom management. The clinical endpoint was an SRI of 4 with no new British Isles Lupus Activity Guide (BILAG) As and no increase in Physician Global Assessment score of >0.3 with tapering of prednisone to 10 mg or less by 20 weeks. RESULTS Of six patients, five (83.3%; 95% CI 35.9% to 99.6%) achieved the clinical endpoint of an SRI of 4. Adverse events were minimal. Mechanistic studies revealed significant reductions in CD27IgD double negative B cells, switched memory B cells and activated naïve B cells, with increased transitional B cells in the five patients who met the endpoint. There was a trend towards decreased autoantibody levels in specific patients. Two patients had increases in their Helios+Treg cells, but no other significant T cell changes were noted. GARP-TGFβ complexes were significantly increased following the MSC infusions. The B cell changes and the GARP-TGFβ increases significantly correlated with changes in SLEDAI scores. CONCLUSION This phase 1 trial suggests that umbilical cord (UC) MSC infusions are very safe and may have efficacy in lupus. The B cell and GARP-TGFβ changes provide novel insight into mechanisms by which MSCs may impact disease. TRIAL REGISTRATION NUMBER NCT03171194.
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Affiliation(s)
- Diane L Kamen
- Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Caroline Wallace
- Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Zihai Li
- Department of Medicine, Division of Hematology/Oncology, Ohio State Wexner Medical Center, Columbus, Ohio, USA
| | - Megan Wyatt
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Crystal Paulos
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Chungwen Wei
- University of Rochester Medical Center, Rochester, New York, USA
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Bethany J Wolf
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Paul J Nietert
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Gary Gilkeson
- Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA
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Singhatanadgit W, Kitpakornsanti S, Toso M, Pavasant P. IFNγ-primed periodontal ligament cells regulate T-cell responses via IFNγ-inducible mediators and ICAM-1-mediated direct cell contact. ROYAL SOCIETY OPEN SCIENCE 2022; 9:220056. [PMID: 35911203 PMCID: PMC9326268 DOI: 10.1098/rsos.220056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 07/04/2022] [Indexed: 06/15/2023]
Abstract
Periodontal ligament (PDL) cells help maintain tissue homeostasis by balancing PDL tissue inflammation and regeneration. However, the mechanisms by which interferon γ (IFNγ) modulate this process are not yet fully understood. The present study aimed to examine the effect of primed and non-primed PDL cells with IFNγ on the viability and differentiation of T lymphocytes and its functional consequences. The results showed that IFNγ-primed PDL cells possessed enhanced immunosuppression by suppressing T-lymphocyte viability and directing T-lymphocyte differentiation towards a higher T helper (Th) Th2/Th1 ratio. Suppression of T-cell viability was mainly mediated by IFNγ-inducible secreted mediators, which was prevented in the presence of direct cell contact, probably by intercellular adhesion molecule-1 (ICAM-1)-induced PI3 K-mediated transforming growth factor β1 expression in PDL cells. By contrast, ICAM-1 activation augmented IFNγ-induced IFNγ and interleukin-6 expression in PDL cells, which in turn modulated T-cell differentiation. The resulting interaction between these two cell types activated macrophage and suppressed osteoclast differentiation. In conclusion, the results have shown, for the first time to our knowledge, that primed and non-primed PDL cells with IFNγ differentially control T-cell responses via IFNγ-inducible mediators and ICAM-1-mediated direct cell contact, suggesting the role of PDL cells in shifting an inflammatory phase towards a regenerative phase.
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Affiliation(s)
- Weerachai Singhatanadgit
- Oral and Maxillofacial Surgery Unit, Faculty of Dentistry, Thammasat University, Rangsit Campus, Pathumthani, Thailand
- Research Unit in Mineralized Tissue Reconstruction, Thammasat University, Rangsit Campus, Pathumthani, Thailand
| | - Setthawut Kitpakornsanti
- Research Unit in Mineralized Tissue Reconstruction, Thammasat University, Rangsit Campus, Pathumthani, Thailand
| | - Montree Toso
- Research Unit in Mineralized Tissue Reconstruction, Thammasat University, Rangsit Campus, Pathumthani, Thailand
- Stem Cell for Life Research Center, Greater Pharma Manufacturing Co. Ltd, Nakhon Pathom, Thailand
| | - Prasit Pavasant
- Center of Excellence in Regenerative Dentistry, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
- Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
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10
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Kuske M, Haist M, Jung T, Grabbe S, Bros M. Immunomodulatory Properties of Immune Checkpoint Inhibitors-More than Boosting T-Cell Responses? Cancers (Basel) 2022; 14:1710. [PMID: 35406483 PMCID: PMC8996886 DOI: 10.3390/cancers14071710] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/24/2022] [Accepted: 03/24/2022] [Indexed: 12/11/2022] Open
Abstract
The approval of immune checkpoint inhibitors (ICI) that serve to enhance effector T-cell anti-tumor responses has strongly improved success rates in the treatment of metastatic melanoma and other tumor types. The currently approved ICI constitute monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein (CTLA)-4 and anti-programmed cell death (PD)-1. By this, the T-cell-inhibitory CTLA-4/CD80/86 and PD-1/PD-1L/2L signaling axes are inhibited. This leads to sustained effector T-cell activity and circumvents the immune evasion of tumor cells, which frequently upregulate PD-L1 expression and modulate immune checkpoint molecule expression on leukocytes. As a result, profound clinical responses are observed in 40-60% of metastatic melanoma patients. Despite the pivotal role of T effector cells for triggering anti-tumor immunity, mounting evidence indicates that ICI efficacy may also be attributable to other cell types than T effector cells. In particular, emerging research has shown that ICI also impacts innate immune cells, such as myeloid cells, natural killer cells and innate lymphoid cells, which may amplify tumoricidal functions beyond triggering T effector cells, and thus improves clinical efficacy. Effects of ICI on non-T cells may additionally explain, in part, the character and extent of adverse effects associated with treatment. Deeper knowledge of these effects is required to further develop ICI treatment in terms of responsiveness of patients to treatment, to overcome resistance to ICI and to alleviate adverse effects. In this review we give an overview into the currently known immunomodulatory effects of ICI treatment in immune cell types other than the T cell compartment.
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Affiliation(s)
| | | | | | | | - Matthias Bros
- Department of Dermatology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.K.); (M.H.); (T.J.); (S.G.)
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Saeedi M, Nezhad MS, Mehranfar F, Golpour M, Esakandari MA, Rashmeie Z, Ghorbani M, Nasimi F, Hoseinian SN. Biological Aspects and Clinical Applications of Mesenchymal Stem Cells: Key Features You Need to be Aware of. Curr Pharm Biotechnol 2021; 22:200-215. [PMID: 32895040 DOI: 10.2174/1389201021666200907121530] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 11/22/2022]
Abstract
Mesenchymal Stem Cells (MSCs), a form of adult stem cells, are known to have a selfrenewing property and the potential to specialize into a multitude of cells and tissues such as adipocytes, cartilage cells, and fibroblasts. MSCs can migrate and home to the desired target zone where inflammation is present. The unique characteristics of MSCs in repairing, differentiation, regeneration, and the high capacity of immune modulation have attracted tremendous attention for exerting them in clinical purposes, as they contribute to the tissue regeneration process and anti-tumor activity. The MSCs-based treatment has demonstrated remarkable applicability towards various diseases such as heart and bone malignancies, and cancer cells. Importantly, genetically engineered MSCs, as a stateof- the-art therapeutic approach, could address some clinical hurdles by systemic secretion of cytokines and other agents with a short half-life and high toxicity. Therefore, understanding the biological aspects and the characteristics of MSCs is an imperative issue of concern. Herein, we provide an overview of the therapeutic application and the biological features of MSCs against different inflammatory diseases and cancer cells. We further shed light on MSCs' physiological interaction, such as migration, homing, and tissue repairing mechanisms in different healthy and inflamed tissues.
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Affiliation(s)
- Mohammad Saeedi
- Department of Laboratory Science, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Muhammad S Nezhad
- Stem Cells and Regenerative Medicine Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mehranfar
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahdieh Golpour
- School of Paramedical Sciences, Semnan University of Medical Sciences, Sorkheh, Semnan, Iran
| | - Mohammad A Esakandari
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Zahra Rashmeie
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Maryam Ghorbani
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Nasimi
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Seyed N Hoseinian
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
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Sotoodehnejadnematalahi F, Moghadasali R, Hajinasrollah M, Ehsani E, Hajizadeh-Saffar E, Sodeifi N, Saidi R, Zarrabi M, Farzanehkhah M, Sadeghi B, Baharvand H, Aghdami N. Immunomodulatory Activity of Human Bone Marrow and Adipose-Derived Mesenchymal Stem Cells Prolongs Allogenic Skin Graft Survival in Nonhuman Primates. CELL JOURNAL 2021; 23:1-13. [PMID: 33650815 PMCID: PMC7944119 DOI: 10.22074/cellj.2021.6895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 11/09/2019] [Indexed: 11/04/2022]
Abstract
Objective In the present study, we examined the tolerance-inducing effects of human adipose-derived mesenchymal stem cells (hAD-MSCs) and bone marrow-derived MSCs (hBM-MSCs) on a nonhuman primate model of skin transplantation. Materials and Methods In this experimental study, allogenic and xenogeneic of immunomodulatory properties of human AD-MSCs and BM-MSCs were evaluated by mixed lymphocyte reaction (MLR) assays. Human MSCs were obtained from BM or AD tissues (from individuals of either sex with an age range of 35 to 65 years) and intravenously injected (2×106 MSCs/kg) after allogeneic skin grafting in a nonhuman primate model. The skin sections were evaluated by H and E staining for histopathological evaluations, particularly inflammation and rejection reaction of grafts after 96 hours of cell injection. At the mRNA and protein levels, cellular mediators of inflammation, such as CD4+IL-17+ (T helper 17; Th17) and CD4+INF-γ+ (T helper 1, Th1) cells, along with CD4+FoxP3+ cells (Treg), as the mediators of immunomodulation, were measured by RT-PCR and flow cytometry analyses. Results A significant Treg cells expansion was observed in MSCs-treated animals which reached the zenith at 24 hours and remained at a high concentration for 96 hours; however, Th1 and Th17 cells were significantly decreased. Our results showed that human MSCs significantly decrease Th1 and Th17 cell proliferation by decreasing interleukin-17 (IL-17) and interferon-γ (INF-γ) production and significantly increase Treg cell proliferation by increasing FoxP3 production. They also extend the allogenic skin graft survival in nonhuman primates. Histological evaluations showed no obvious presence of inflammatory cells or skin redness or even bulging after MSCs injection up to 96 hours, compared to the group without MSCs. There were no significant differences between hBM-MSCs and hAD-MSCs in terms of histopathological scores and inflammatory responses (P<0.05). Conclusion It seems that MSCs could be regarded as a valuable immunomodulatory tool to reduce the use of immunosuppressive agents.
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Affiliation(s)
| | - Reza Moghadasali
- Department of Stem Cells and Developmental Biology, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. .,Department of Regenerative Medicine, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Mostafa Hajinasrollah
- Department of Stem Cells and Developmental Biology, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Ehsan Ehsani
- Department of Stem Cells and Developmental Biology, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Biology, Roudehen Branch, Islamic Azad University, Roudehen, Iran
| | - Ensiyeh Hajizadeh-Saffar
- Department of Regenerative Medicine, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Sodeifi
- Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Reza Saidi
- Department of Surgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Zarrabi
- Royan Stem Cell Technology Company, Cord Blood Bank, Tehran, Iran
| | | | - Bahareh Sadeghi
- Royan Stem Cell Technology Company, Cord Blood Bank, Tehran, Iran
| | - Hossein Baharvand
- Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran.,Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Nasser Aghdami
- Department of Developmental Biology, University of Science and Culture, Tehran, Iran
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Kuca-Warnawin E, Janicka I, Bonek K, Kontny E. Modulatory Impact of Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients on T Helper Cell Differentiation. Cells 2021; 10:cells10020280. [PMID: 33573252 PMCID: PMC7912699 DOI: 10.3390/cells10020280] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/23/2021] [Accepted: 01/25/2021] [Indexed: 12/17/2022] Open
Abstract
The domination of pro-inflammatory Th subsets (Th1, Th17) is characteristic of ankylosing spondylitis (AS). Mesenchymal stem cells (MSC) were reported to normalize Th imbalance, but whether MSCs from AS adipose tissue (AS/ASCs) possess such properties is unknown. We examined AS/ASCs' impact on Th-cell differentiation, using healthy donors ASCs (HD/ASCs) as a control. The assessment of the expression of transcription factors defining Th1 (T-bet), Th2 (GATA3), Th17 (RORc), and Treg (FoxP3) subsets by quantitative RT-PCR, the concentrations of subset-specific cytokines by ELISA, and Treg (CD4+CD25highFoxP3+) formation by flow cytometry, were performed in the co-cultures of ASCs with activated CD4+ T cells or peripheral blood mononuclear cells (PBMCs). AS/ASCs and HD/ASCs exerted similar immunomodulatory effects. Acting directly on CD4+ T cells, ASCs decreased the T-bet/GATA3 and RORc/FoxP3 ratios, diminished Treg formation, but increase IFNγ and IL-17AF production, while ASCs co-cultured with PBMCs enhanced Treg generation and reduced IFNγ release. ASCs failed to up-regulate the anti-inflammatory IL-10 and TGFβ. AS/ASCs' impact on allogeneic and autologous PBMCs was similar. In conclusion, to shift Th differentiation to a functional anti-inflammatory direction, ASCs require accessory cell support, whereas their direct effect may be pro-inflammatory. Because ASCs neither inhibit IL-17AF nor up-regulate anti-inflammatory cytokines, their usefulness for AS patients' treatment remains uncertain.
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Affiliation(s)
- Ewa Kuca-Warnawin
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology, and Rehabilitation, 02-637 Warsaw, Poland; (I.J.); (E.K.)
- Correspondence: ; Tel.: +48-22-6-709-260
| | - Iwona Janicka
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology, and Rehabilitation, 02-637 Warsaw, Poland; (I.J.); (E.K.)
| | - Krzysztof Bonek
- Department of Rheumatology, National Institute of Geriatrics, Rheumatology, and Rehabilitation, 02-637 Warsaw, Poland;
| | - Ewa Kontny
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology, and Rehabilitation, 02-637 Warsaw, Poland; (I.J.); (E.K.)
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Human Adipose Tissue-Derived Mesenchymal Stromal Cells Inhibit CD4+ T Cell Proliferation and Induce Regulatory T Cells as Well as CD127 Expression on CD4+CD25+ T Cells. Cells 2021; 10:cells10010058. [PMID: 33401501 PMCID: PMC7824667 DOI: 10.3390/cells10010058] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/22/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSC) exert their immunomodulatory potential on several cell types of the immune system, affecting and influencing the immune response. MSC efficiently inhibit T cell proliferation, reduce the secretion of pro-inflammatory cytokines, limit the differentiation of pro-inflammatory Th subtypes and promote the induction of regulatory T cells (Treg). In this study, we analyzed the immunomodulatory potential of human adipose tissue-derived MSC (ASC), on CD4+ T cells, addressing potential cell-contact dependency in relation to T cell receptor stimulation of whole human peripheral blood mononuclear cells (PBMC). ASC were cultured with not stimulated or anti-CD3/CD28-stimulated PBMC in direct and transwell cocultures; PBMC alone were used as controls. After 7 days, cocultures were harvested and we analyzed: (1) the inhibitory potential of ASC on CD4+ cell proliferation and (2) phenotypic changes in CD4+ cells in respect of Treg marker (CD25, CD127 and FoxP3) expression. We confirmed the inhibitory potential of ASC on CD4+ cell proliferation, which occurs upon PBMC stimulation and is mediated by indoleamine 2,3-dioxygenase. Importantly, ASC reduce both pro- and anti-inflammatory cytokine secretion, without indications on specific Th differentiation. We found that stimulation induces CD25 expression on CD4+ cells and that, despite inhibiting overall CD4+ cell proliferation, ASC can specifically induce the proliferation of CD4+CD25+ cells. We observed that ASC induce Treg (CD4+CD25+CD127−FoxP3+) only in not stimulated cocultures and that ASC increase the ratio of CD4+CD25+CD127+FoxP3− cells at the expense of CD4+CD25+CD127−FoxP3− cells. Our study provides new insights on the interplay between ASC and CD4+ T cells, proposing that ASC-dependent induction of Treg depends on PBMC activation which affects the balance between the different subpopulations of CD4+CD25+ cells expressing CD127 and/or FoxP3.
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15
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Placental Mesenchymal Stromal Cells (PMSCs) and PMSC-Derived Extracellular Vesicles (PMSC-EVs) Attenuated Renal Fibrosis in Rats with Unilateral Ureteral Obstruction (UUO) by Regulating CD4 + T Cell Polarization. Stem Cells Int 2020; 2020:2685820. [PMID: 32774389 PMCID: PMC7396053 DOI: 10.1155/2020/2685820] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 04/22/2020] [Accepted: 06/09/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose Recent evidence has shown that CD4+ T helper (Th) cells are involved in renal inflammation and fibrosis. However, whether renal fibrosis can be alleviated by intervening in the polarization of CD4+ T cells remains unknown. Our research investigated the effects of intravenously administered placenta mesenchymal stromal cells (PMSCs) or treatment with extracellular EVs (EVs) derived from PMSCs (PMSC-EVs) on the polarization of CD4+ T cells in rats with unilateral ureteral obstruction (UUO). We further verified how PMSCs affect inflammatory factor secretion and the levels of regulatory T (Treg) and Th17 CD4+ T cells in vitro. Materials and Methods We evaluated renal interstitial inflammation and fibrosis by pathological section staining, tested the polarization of CD4+ T cells (Th17 and Treg phenotypes) by flow cytometry (FCM) and immunohistochemistry, and detected the cytokines secreted by CD4+ T cells by enzyme-linked immunosorbent assay (ELISA). Results Compared with that of control rats, the renal tissue of PMSC-treated rats exhibited lower renal Masson scores and more Foxp3+ cell infiltration, with a significantly decreased IL17A+CD4+ T cell/CD4+ T cell ratio and a significantly elevated anti-inflammatory cytokine (IL-10) level. When CD4+ T cells were cocultured with PMSCs, CD4+IL17A+ cell percentages were decreased in a UUO model after 7 days of coculture with PMSCs. The secretion of TGF-β and IL-10 was significantly increased (P < 0.05), while the secretion of IFN-γ, IL-17, and IL-6 was significantly decreased (P < 0.05) in the PMSC coculture group. Moreover, after treatment with PMSC-EVs, tubulointerstitial fibrosis was alleviated, and Foxp3+/IL-17+ cell infiltration was increased in the kidneys of UUO model animals on day 7. Conclusions PMSCs can convert the inflammatory environment into an anti-inflammatory environment by affecting the polarization of CD4+ T cells and macrophages, inhibiting the inflammatory factors IFN-γ and IL-17, and upregulating the expression of the anti-inflammatory factors TGF-β and IL-10, ultimately leading to renal protection. Such functions may be mediated by the paracrine activity of PMSC-EVs.
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Sergeant E, Buysse M, Devos T, Sprangers B. Multipotent mesenchymal stromal cells in kidney transplant recipients: The next big thing? Blood Rev 2020; 45:100718. [PMID: 32507576 DOI: 10.1016/j.blre.2020.100718] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 04/13/2020] [Accepted: 05/11/2020] [Indexed: 12/20/2022]
Abstract
Bone marrow-derived multipotent mesenchymal stromal cells (BM-MSCs) are non-haematopoietic cells present in the bone marrow stroma. They have the potential to modulate immune responses and exhibit a capacity to promote immune tolerance. Although the efficacy of immunosuppressive drugs has improved significantly, thereby ameliorating renal graft outcome, the use of these drugs still carries an increased risk of malignancies and opportunistic infections, and sometimes fail to prevent chronic allograft rejection or recurrence of the original kidney disease. As such, there is strong interest in ways to induce immune tolerance and thereby tempering or avoiding conventional immunosuppressive drugs. Cellular immunomodulation by MSCs can create a new way to induce transplant tolerance. This review will give a critical overview of the use of BM-MSCs as a cell-based immunosuppressive therapy in kidney transplant recipients. In vitro studies revealed several mechanisms that can clarify the immunomodulatory potential of BM-MSCs. Several clinical studies showed that BM-MSCs can modulate T-cell proliferation and can alter the ratio of T-cell subsets, favoring immune tolerance. However, this immunomodulation was often not associated with better clinical outcome during follow-up when compared to control groups. Some clinical studies found that BM-MSCs allow a reduction in dose of conventional immunosuppressive drugs and prevent acute graft dysfunction. Most clinical studies emphasized that BM-MSC infusion was safe. This review suggests that the use of BM-MSCs as cell-based immunosuppression therapy in kidney transplant recipients has potential, however some caution regarding their clinical use is appropriate. Mechanisms by which BM-MSCs induce transplant tolerance and factors that can alter their functionality need to be analyzed in more detail before clinical use.
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Affiliation(s)
- Elien Sergeant
- Division of Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
| | - Malicorne Buysse
- Division of Hematology, University Hospitals Ghent, Ghent, Belgium.
| | - Timothy Devos
- Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium; Division of Hematology, University Hospitals Leuven, Leuven, Belgium.
| | - Ben Sprangers
- Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium; Division of Nephrology, University Hospitals Leuven, Leuven, Belgium.
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Effect of Timing and Complement Receptor Antagonism on Intragraft Recruitment and Protolerogenic Effects of Mesenchymal Stromal Cells in Murine Kidney Transplantation. Transplantation 2020; 103:1121-1130. [PMID: 30801518 DOI: 10.1097/tp.0000000000002611] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) have protolerogenic effects in renal transplantation, but they induce long-term regulatory T cells (Treg)-dependent graft acceptance only when infused before transplantation. When given posttransplant, MSCs home to the graft where they promote engraftment syndrome and do not induce Treg. Unfortunately, pretransplant MSC administration is unfeasible in deceased-donor kidney transplantation. METHODS To make MSCs a therapeutic option also for deceased organ recipients, we tested whether MSC infusion at the time of transplant (day 0) or posttransplant (day 2) together with inhibition of complement receptors prevents engraftment syndrome and allows their homing to secondary lymphoid organs for promoting tolerance. We analyzed intragraft and splenic MSC localization, graft survival, and alloimmune response in mice recipients of kidney allografts and syngeneic MSCs given on day 0 or on posttransplant day 2. C3a receptor (C3aR) or C5a receptor (C5aR) antagonists were administered to mice in combination with the cells or were used together to treat MSCs before infusion. RESULTS Syngeneic MSCs given at day 0 homed to the spleen increased Treg numbers and induced long-term graft acceptance. Posttransplant MSC infusion, combined with a short course of C3aR or C5aR antagonist or administration of MSCs pretreated with C3aR and C5aR antagonists, prevented intragraft recruitment of MSCs and graft inflammation, inhibited antidonor T-cell reactivity, but failed to induce Treg, resulting in mild prolongation of graft survival. CONCLUSIONS These data support testing the safety/efficacy profile of administering MSCs on the day of transplant in deceased-donor transplant recipients and indicate that complement is crucial for MSC recruitment into the kidney allograft.
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Khoury O, Atala A, Murphy SV. Stromal cells from perinatal and adult sources modulate the inflammatory immune response in vitro by decreasing Th1 cell proliferation and cytokine secretion. Stem Cells Transl Med 2019; 9:61-73. [PMID: 31638323 PMCID: PMC6954711 DOI: 10.1002/sctm.19-0123] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022] Open
Abstract
Many immune-mediated conditions are associated with a dysregulated imbalance toward a Th1 response leading to disease onset, severity, and damage. Many of the therapies such as immunomodulators or anti-TNF-α antibodies often fall short in preventing disease progression and ameliorating disease conditions. Thus, new therapies that can target inflammatory environments would have a major impact in preventing the progression of inflammatory diseases. We investigated the role of human stromal cells derived from the amniotic fluid (AFSCs), the placenta (PLSCs), and bone marrow-derived mesenchymal stromal cells (BM-MSCs) in modulating the inflammatory response of in vitro-stimulated circulating blood-derived immune cells. Immune cells were isolated from the blood of healthy individuals and stimulated in vitro with antigens to activate inflammatory responses to stimuli. AFSC, BM-MSCs, and PLSCs were cocultured with stimulated leukocytes, neutrophils, or lymphocytes. Inflammatory cytokine production, neutrophil migration, enzymatic degranulation, T cell proliferation, and subsets were evaluated. Coculture of all three stromal cell types decreased the gene expression of inflammatory cytokines and enzymes such as IL-1β, IFN-γ, TNF-α, neutrophil elastase, and the transcription factor NF-κB in lipopolysaccharide-stimulated leukocytes. With isolated phytohemagglutinin-stimulated peripheral blood mononuclear cells, cells coculture leads to a decrease in lymphocyte proliferation. This effect correlated with decreased numbers of Th1 lymphocytes and decreased secreted levels of IFN-γ.
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Affiliation(s)
- Oula Khoury
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Sean V Murphy
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
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Intercellular adhesion molecule-1 enhances the therapeutic effects of MSCs in a dextran sulfate sodium-induced colitis models by promoting MSCs homing to murine colons and spleens. Stem Cell Res Ther 2019; 10:267. [PMID: 31443680 PMCID: PMC6708236 DOI: 10.1186/s13287-019-1384-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 08/04/2019] [Accepted: 08/14/2019] [Indexed: 12/15/2022] Open
Abstract
Background To investigate the therapeutic effect of intercellular adhesion molecule (ICAM)-1-modified mesenchymal stem cells (MSCs) in a mouse model of inflammatory bowel disease (IBD) induced by dextran sulfate sodium. Methods Primary MSCs and ICAM-1-overexpressing MSCs (C3 cells) were generated in vitro. The IBD mouse model was induced with drinking water containing dextran sulfate sodium for 7 days. For stem cell therapy, mice were randomly assigned to six experimental groups: the control group, IBD group, primary MSC group, C3 group, C3-vector group, and C3-ICAM-1 group. Mice were given a single injection of 1 × 106 primary MSCs or gene-modified MSCs via the tail vein on day 3 of DDS administration. The general conditions of the mice in each group were observed. Additionally, the pathological changes in the colon were observed and scored. Primary MSCs and gene-modified MSCs were stained with the fluorescent dye CM-DIL before injection into the tail vein of mice. The distribution of infused cells in IBD mice was observed in frozen sections. Mechanistically, the polarization of Th1, Th2, Th17, and regulatory T cells (Tregs) in the spleen was determined by flow cytometry. Moreover, the mRNA expression levels of IBD-related immune factors in splenocytes were measured by quantitative PCR. Results A single injection of MSCs promoted general recovery and reduced pathological damage in IBD mice. Additionally, ICAM-1-overexpressing MSCs had stronger therapeutic effects than ICAM-1low MSCs. Furthermore, the in vivo distribution analysis results indicated that a higher number of ICAM-1-overexpressing MSCs homed to the colon and spleen of IBD mice. Moreover, the delivery of ICAM-1 overexpressing MSCs decreased the numbers of Th1 and Th17 cells but increased the number of Tregs in the spleen of IBD mice. The quantitative PCR analysis results revealed that an infusion of ICAM-1-overexpressing MSCs influenced the expression of spleen-derived immune factors by remarkably reducing the mRNA levels of IFN-γ and IL-17A and increasing the mRNA level of Foxp3. Conclusions Our results demonstrate that ICAM-1-modified mesenchymal stem cells (MSCs) remarkably alleviate inflammatory damage in IBD mice by promoting MSC homing to the target and immune organs. The findings suggest that ICAM-1 is required to maintain the therapeutic effects of MSCs in IBD treatment and identified a novel role of ICAM-1 in inflammatory diseases. Electronic supplementary material The online version of this article (10.1186/s13287-019-1384-9) contains supplementary material, which is available to authorized users.
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Podestà MA, Remuzzi G, Casiraghi F. Mesenchymal Stromal Cells for Transplant Tolerance. Front Immunol 2019; 10:1287. [PMID: 31231393 PMCID: PMC6559333 DOI: 10.3389/fimmu.2019.01287] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 05/21/2019] [Indexed: 12/18/2022] Open
Abstract
In solid organ transplantation lifelong immunosuppression exposes transplant recipients to life-threatening complications, such as infections and malignancies, and to severe side effects. Cellular therapy with mesenchymal stromal cells (MSC) has recently emerged as a promising strategy to regulate anti-donor immune responses, allowing immunosuppressive drug minimization and tolerance induction. In this review we summarize preclinical data on MSC in solid organ transplant models, focusing on potential mechanisms of action of MSC, including down-regulation of effector T-cell response and activation of regulatory pathways. We will also provide an overview of available data on safety and feasibility of MSC therapy in solid organ transplant patients, highlighting the issues that still need to be addressed before establishing MSC as a safe and effective tolerogenic cell therapy in transplantation.
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Affiliation(s)
- Manuel Alfredo Podestà
- Department of Molecular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.,Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Giuseppe Remuzzi
- Department of Molecular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Federica Casiraghi
- Department of Molecular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Bertheuil N, Chaput B, Ménard C, Varin A, Laloze J, Watier E, Tarte K. Adipose mesenchymal stromal cells: Definition, immunomodulatory properties, mechanical isolation and interest for plastic surgery. ANN CHIR PLAST ESTH 2019; 64:1-10. [DOI: 10.1016/j.anplas.2018.07.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 07/13/2018] [Indexed: 12/14/2022]
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Razmkhah M, Abtahi S, Ghaderi A. Mesenchymal Stem Cells, Immune Cells and Tumor Cells Crosstalk: A Sinister Triangle in the Tumor Microenvironment. Curr Stem Cell Res Ther 2019; 14:43-51. [PMID: 30112998 DOI: 10.2174/1574888x13666180816114809] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 08/08/2018] [Accepted: 08/09/2018] [Indexed: 02/07/2023]
Abstract
Mesenchymal Stem Cells [MSCs] are a heterogeneous population of fibroblast-like cells which maintain self-renewability and pluripotency. Many studies have demonstrated the immunomodulatory effects of MSCs on the innate and adaptive immune cells. As a result of interactions with tumor cells, microenvironment and immune-stimulating milieu, MSCs contribute to tumor progression by several mechanisms, including sustained proliferative signal in cancer stem cells [CSCs], inhibition of tumor cell apoptosis, transition to tumor-associated fibroblasts [TAFs], promotion of angiogenesis, stimulation of epithelial-mesenchymal transition [EMT], suppression of immune responses, and consequential promotion of tumor metastasis. Here, we present an overview of the latest findings on Janusfaced roles that MSCs play in the tumor microenvironment [TME], with a concise focus on innate and adaptive immune responses.
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Affiliation(s)
- Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shabnam Abtahi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Ghaderi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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23
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Dorraji SE, Hovd AMK, Kanapathippillai P, Bakland G, Eilertsen GØ, Figenschau SL, Fenton KA. Mesenchymal stem cells and T cells in the formation of Tertiary Lymphoid Structures in Lupus Nephritis. Sci Rep 2018; 8:7861. [PMID: 29777158 PMCID: PMC5959845 DOI: 10.1038/s41598-018-26265-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 05/09/2018] [Indexed: 12/13/2022] Open
Abstract
Tertiary lymphoid structures (TLS) develop in the kidneys of lupus-prone mice and systemic lupus erythematosus (SLE) patients with lupus nephritis (LN). Here we investigated the presence of mesenchymal stem cells (MSCs) in the development of TLS in murine LN, as well as the role of human MSCs as lymphoid tissue organizer (LTo) cells on the activation of CD4+ T cells from three groups of donors including Healthy, SLE and LN patients. Mesenchymal stem like cells were detected within the pelvic wall and TLS in kidneys of lupus-prone mice. An increase in LTβ, CXCL13, CCL19, VCAM1 and ICAM1 gene expressions were detected during the development of murine LN. Human MSCs stimulated with the pro-inflammatory cytokines TNF-α and IL-1β significantly increased the expression of CCL19, VCAM1, ICAM1, TNF-α, and IL-1β. Stimulated MSCs induced proliferation of CD4+ T cells, but an inhibitory effect was observed when in co-culture with non-stimulated MSCs. A contact dependent increase in Th2 and Th17 subsets were observed for T cells from the Healthy group after co-culture with stimulated MSCs. Our data suggest that tissue-specific or/and migratory MSCs could have pivotal roles as LTo cells in accelerating early inflammatory processes and initiating the formation of kidney specific TLS in chronic inflammatory conditions.
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Affiliation(s)
- S Esmaeil Dorraji
- RNA and Molecular Pathology Research Group, Institute of Medical Biology, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Aud-Malin K Hovd
- RNA and Molecular Pathology Research Group, Institute of Medical Biology, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Premasany Kanapathippillai
- RNA and Molecular Pathology Research Group, Institute of Medical Biology, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Gunnstein Bakland
- University Hospital of Northern Norway, Tromsø, Norway.,Molecular Inflammatory Research Group, Institute of Clinical Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Gro Østli Eilertsen
- University Hospital of Northern Norway, Tromsø, Norway.,Molecular Inflammatory Research Group, Institute of Clinical Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Stine L Figenschau
- RNA and Molecular Pathology Research Group, Institute of Medical Biology, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Kristin A Fenton
- RNA and Molecular Pathology Research Group, Institute of Medical Biology, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway.
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24
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Erpicum P, Rowart P, Poma L, Krzesinski JM, Detry O, Jouret F. Administration of mesenchymal stromal cells before renal ischemia/reperfusion attenuates kidney injury and may modulate renal lipid metabolism in rats. Sci Rep 2017; 7:8687. [PMID: 28819187 PMCID: PMC5561049 DOI: 10.1038/s41598-017-08726-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 07/17/2017] [Indexed: 12/22/2022] Open
Abstract
Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodent models. The mechanisms of such nephro-protection remain largely unknown. Furthermore, the optimal timing of MSC administration has been poorly investigated. Here, we compare the impact of MSC injection 7 days before (MSCD - 7) versus 1 day after (MSCD + 1) renal I/R in rats. Control groups received equivalent volumes of saline at similar time-points (SD - 7 and SD + 1). Right nephrectomy was performed, and left renal ischemia lasted 45 min. After 48-hour reperfusion, we observed significantly improved renal function parameters, reduced apoptotic index and neutrophil/macrophage infiltration in kidney parenchyma, and lower expression of tubular damage markers and pro-inflammatory cytokines in MSCD - 7 in comparison to MSCD + 1 and saline control groups. Next, comparative high-throughput RNA sequencing of MSCD - 7 vs. SD - 7 non-ischemic right kidneys highlighted significant down-regulation of fatty acid biosynthesis and up-regulation of PPAR-α pathway. Such a preferential regulation towards lipid catabolism was associated with decreased levels of lipid peroxidation products, i.e. malondialdehyde and 4-hydroxy-2-nonenal, in MSCD - 7 versus SD - 7 ischemic kidneys. Our findings suggest that MSC pretreatment may exert protective effects against renal I/R by modulating lipid metabolism in rats.
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Affiliation(s)
- Pauline Erpicum
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium.,Division of Nephrology, University of Liège Hospital (ULg CHU), Liège, Belgium
| | - Pascal Rowart
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium
| | - Laurence Poma
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium
| | - Jean-Marie Krzesinski
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium.,Division of Nephrology, University of Liège Hospital (ULg CHU), Liège, Belgium
| | - Olivier Detry
- Department of Abdominal Surgery and Transplantation, University of Liège Hospital (ULg CHU), Liège, Belgium.,Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), CREDEC Unit, University of Liège, Liège, Belgium
| | - François Jouret
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium. .,Division of Nephrology, University of Liège Hospital (ULg CHU), Liège, Belgium.
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25
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Sharma J, Hampton JM, Valiente GR, Wada T, Steigelman H, Young MC, Spurbeck RR, Blazek AD, Bösh S, Jarjour WN, Young NA. Therapeutic Development of Mesenchymal Stem Cells or Their Extracellular Vesicles to Inhibit Autoimmune-Mediated Inflammatory Processes in Systemic Lupus Erythematosus. Front Immunol 2017; 8:526. [PMID: 28539924 PMCID: PMC5423896 DOI: 10.3389/fimmu.2017.00526] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Accepted: 04/19/2017] [Indexed: 12/12/2022] Open
Abstract
Since being discovered over half a century ago, mesenchymal stem cells (MSCs) have been investigated extensively to characterize their cellular and physiological influences. MSCs have been shown to possess immunosuppressive capacity through inhibiting lymphocyte activation/proliferation and proinflammatory cytokine secretion while simultaneously demonstrating limited allogenic reactivity, which subsequently led to the evaluation of therapeutic feasibility to treat inflammatory diseases. Although regulatory constraints have restricted MSC development pharmacologically, limited clinical studies have shown encouraging results using MSC infusions to treat systemic lupus erythematosus (SLE); but, more trials will have to be performed to conclusively determine the clinical efficacy of MSCs to treat SLE. Moreover, there are some data to suggest that MSCs possess tumorigenic potential and that the immunosuppressive influence can be dramatically affected by both donor variability and ex vivo expansion. Given that recent studies have found that the immunosuppressive effects of MSCs are a result, at least in part, to extracellular vesicle (EV) secretion, the use of MSC-derived EVs has been suggested as a cell-free therapeutic alternative. Despite the positive data observed using EVs isolated from human MSCs to suppress inflammatory responses in vitro and in inhibiting autoimmune disease pathogenesis in preclinical work, there are no studies to date examining EVs from MSCs to treat SLE in humans or animal models. Considering that EVs are not subject to the strict regulatory constraints of stem cell-based pharmacological development and are more readily standardized with regard to industrial-scale production and storage, this review outlines the anti-inflammatory biology of MSCs and the scientific evidence supporting the potential use of EVs derived from human MSCs to treat patients with SLE.
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Affiliation(s)
- Juhi Sharma
- Division of Rheumatology and Immunology, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, USA
| | - Jeffrey M Hampton
- Division of Rheumatology and Immunology, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, USA
| | - Giancarlo R Valiente
- Division of Rheumatology and Immunology, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, USA
| | - Takuma Wada
- Division of Rheumatology and Immunology, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, USA
| | - Holly Steigelman
- Division of Rheumatology and Immunology, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, USA
| | | | | | | | - Steffi Bösh
- Université de Nantes, Immuno-endocrinologie Cellulaire et Moléculaire, Nantes, France
| | - Wael N Jarjour
- Division of Rheumatology and Immunology, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, USA
| | - Nicholas A Young
- Division of Rheumatology and Immunology, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, USA
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26
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Mesenchymal Stem Cell Therapy for Inflammatory Skin Diseases: Clinical Potential and Mode of Action. Int J Mol Sci 2017; 18:ijms18020244. [PMID: 28125063 PMCID: PMC5343781 DOI: 10.3390/ijms18020244] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/15/2017] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammatory skin disorders that cause serious deterioration of the quality of life have become one of the major public concerns. Despite their significance, there is no fundamental cure to date. Mesenchymal stem cells (MSCs) possess unique immunomodulatory properties which make them a promising tool for the treatment of various inflammatory diseases. Our recent preclinical and clinical studies have shown that MSCs can be successfully used for the treatment of atopic dermatitis (AD), one of the major inflammatory skin diseases. This observation along with similar reports from other groups revealed the efficacy and underlying mechanisms of MSCs in inflammatory dermatosis. In addition, it has been proposed that cell priming or gene transduction can be novel strategies for the development of next-generation high-efficacy MSCs for treating inflammatory skin diseases. We discuss here existing evidence that demonstrates the regulatory properties of MSCs on immune responses under inflammatory conditions.
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27
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Grégoire C, Lechanteur C, Briquet A, Baudoux É, Baron F, Louis E, Beguin Y. Review article: mesenchymal stromal cell therapy for inflammatory bowel diseases. Aliment Pharmacol Ther 2017; 45:205-221. [PMID: 27878827 DOI: 10.1111/apt.13864] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 06/21/2016] [Accepted: 10/25/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are chronic relapsing diseases in which pro-inflammatory immune cells and cytokines induce intestinal tissue damage and disability. Mesenchymal stromal cells (MSCs) exert powerful immunomodulatory effects and stimulate tissue repair. AIM To review the current data on mesenchymal stromal cell therapy in IBD. METHOD We searched PubMed and 'ClinicalTrials.gov' databases using the terms 'mesenchymal stromal cells', 'mesenchymal stem cell transplantation', 'inflammatory bowel diseases', 'Crohn disease' and 'colitis, ulcerative'. Additional publications were identified from individual article reference lists. RESULTS MSCs include inhibition of Th1/Th17 lymphocytes and recruitment of regulatory T lymphocytes, induction of antigen-presenting cells into a regulatory-like profile, and stimulation of epithelial cell differentiation and proliferation. More than 200 patients with refractory fistulas have been treated with local injections of MSCs, resulting in complete response in more than half, and in overall response in approximately two thirds of patients. In refractory luminal Crohn's disease, 49 cases of systemic MSC infusions have been reported, while trials with autologous MSCs resulted in mitigated responses, studies using allogeneic MSCs were promising, with around 60% of patients experiencing a response and around 40% achieving clinical remission. CONCLUSIONS Mesenchymal stromal cells might represent a promising therapy for IBD, especially for Crohn's disease. There remain many unsolved questions concerning the optimal origin and source of mesenchymal stromal cells, dosage and modalities of administration. Moreover, mesenchymal stromal cells still need to prove their effectiveness compared with conventional treatments in randomised controlled trials.
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Affiliation(s)
- C Grégoire
- Unit of Haematology, Department of Haematology, CHU of Liège, GIGA-I3, University of Liège, Liège, Belgium
| | - C Lechanteur
- Laboratory of Cell and Gene Therapy (LTCG), CHU of Liège, Liège, Belgium
| | - A Briquet
- Laboratory of Cell and Gene Therapy (LTCG), CHU of Liège, Liège, Belgium
| | - É Baudoux
- Laboratory of Cell and Gene Therapy (LTCG), CHU of Liège, Liège, Belgium
| | - F Baron
- Unit of Haematology, Department of Haematology, CHU of Liège, GIGA-I3, University of Liège, Liège, Belgium
| | - E Louis
- Department of Gastroenterology, CHU of Liège, University of Liège, Liège, Belgium
| | - Y Beguin
- Unit of Haematology, Department of Haematology, CHU of Liège, GIGA-I3, University of Liège, Liège, Belgium.,Laboratory of Cell and Gene Therapy (LTCG), CHU of Liège, Liège, Belgium
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28
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Fuenzalida P, Kurte M, Fernández-O'ryan C, Ibañez C, Gauthier-Abeliuk M, Vega-Letter AM, Gonzalez P, Irarrázabal C, Quezada N, Figueroa F, Carrión F. Toll-like receptor 3 pre-conditioning increases the therapeutic efficacy of umbilical cord mesenchymal stromal cells in a dextran sulfate sodium-induced colitis model. Cytotherapy 2016; 18:630-41. [PMID: 27059200 DOI: 10.1016/j.jcyt.2016.02.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 02/01/2016] [Accepted: 02/04/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AIMS Immunomodulatory properties of human umbilical cord-derived mesenchymal stromal cells (UCMSCs) can be differentially modulated by toll-like receptors (TLR) agonists. Here, the therapeutic efficacy of short TLR3 and TLR4 pre-conditioning of UCMSCs was evaluated in a dextran sulfate sodium (DSS)-induced colitis in mice. The novelty of this study is that although modulation of human MSCs activity by TLRs is not a new concept, this is the first time that short TLR pre-conditioning has been carried out in a murine inflammatory model of acute colitis. METHODS C57BL/6 mice were exposed to 2.5% dextran sulfate sodium (DSS) in drinking water ad libitum for 7 days. At days 1 and 3, mice were injected intraperitoneally with 1 × 10(6) UCMSCs untreated or TLR3 and TLR4 pre-conditioned UCMSCs. UCMSCs were pre-conditioned with poly(I:C) for TLR3 and LPS for TLR4 for 1 h at 37°C and 5% CO2. We evaluated clinical signs of disease and body weights daily. At the end of the experiment, colon length and histological changes were assessed. RESULTS poly(I:C) pre-conditioned UCMSCs significantly ameliorated the clinical and histopathological severity of DSS-induced colitis compared with UCMSCs or LPS pre-conditioned UCMSCs. In contrast, infusion of LPS pre-conditioned UCMSCs significantly increased clinical signs of disease, colon shortening and histological disease index in DSS-induced colitis. CONCLUSIONS These results show that short in vitro TLR3 pre-conditioning with poly(I:C) enhances the therapeutic efficacy of UCMSCs, which is a major breakthrough for developing improved treatments to patients with inflammatory bowel disease.
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Affiliation(s)
- Patricia Fuenzalida
- Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile
| | - Mónica Kurte
- Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile
| | - Catalina Fernández-O'ryan
- Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile
| | - Cristina Ibañez
- Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile
| | - Melanie Gauthier-Abeliuk
- Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile
| | - Ana María Vega-Letter
- Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile
| | - Paz Gonzalez
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, University of the Andes, Santiago, Chile; Cells for Cells, Santiago, Chile, Faculty of Medicine, University of the Andes, Santiago, Chile
| | - Carlos Irarrázabal
- Laboratory of Integrative and Molecular Physiology, Faculty of Medicine, University of the Andes, Santiago, Chile
| | - Nataly Quezada
- Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile
| | - Fernando Figueroa
- Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile
| | - Flavio Carrión
- Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile.
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Vega-Letter AM, Kurte M, Fernández-O'Ryan C, Gauthier-Abeliuk M, Fuenzalida P, Moya-Uribe I, Altamirano C, Figueroa F, Irarrázabal C, Carrión F. Differential TLR activation of murine mesenchymal stem cells generates distinct immunomodulatory effects in EAE. Stem Cell Res Ther 2016; 7:150. [PMID: 27724984 PMCID: PMC5057482 DOI: 10.1186/s13287-016-0402-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 08/30/2016] [Indexed: 02/15/2023] Open
Abstract
Background Recently, it has been observed that mesenchymal stem cells (MSCs) can modulate their immunoregulatory properties depending on the specific in-vitro activation of different Toll-like receptors (TLR), such as TLR3 and TLR4. In the present study, we evaluated the effect of polyinosinic:polycytidylic acid (poly(I:C)) and lipopolysaccharide (LPS) pretreatment on the immunological capacity of MSCs in vitro and in vivo. Methods C57BL/6 bone marrow-derived MSCs were pretreated with poly(I:C) and LPS for 1 hour and their immunomodulatory capacity was evaluated. T-cell proliferation and their effect on Th1, Th17, and Treg differentiation/activation were measured. Next, we evaluated the therapeutic effect of MSCs in an experimental autoimmune encephalomyelitis (EAE) model, which was induced for 27 days with MOG35–55 peptide following the standard protocol. Mice were subjected to a single intraperitoneal injection (2 × 106 MSCs/100 μl) on day 4. Clinical score and body weight were monitored daily by blinded analysis. At day 27, mice were euthanized and draining lymph nodes were extracted for Th1, Th17, and Treg detection by flow cytometry. Results Pretreatment of MSCs with poly(I:C) significantly reduced the proliferation of CD3+ T cells as well as nitric oxide secretion, an important immunosuppressive factor. Furthermore, MSCs treated with poly(I:C) reduced the differentiation/activation of proinflammatory lymphocytes, Th1 and Th17. In contrast, MSCs pretreated with LPS increased CD3+ T-cell proliferation, and induced Th1 and Th17 cells, as well as the levels of proinflammatory cytokine IL-6. Finally, we observed that intraperitoneal administration of MSCs pretreated with poly(I:C) significantly reduced the severity of EAE as well as the percentages of Th1 and Th17 proinflammatory subsets, while the pretreatment of MSCs with LPS completely reversed the therapeutic immunosuppressive effect of MSCs. Conclusions Taken together, these data show that pretreatment of MSCs with poly(I:C) improved their immunosuppressive abilities. This may provide an opportunity to better define strategies for cell-based therapies to autoimmune diseases.
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Affiliation(s)
- Ana María Vega-Letter
- Laboratory of Cellular and Molecular Immunology, Faculty of Medicine, Universidad de los Andes, Monseñor Álvaro del Portillo N°12.455, Las Condes, Santiago, 750000, Chile.,Cell Culture Laboratory Animals, School of of Biochemical Engineering, Pontificia Universidad Católica de Valparaíso, Av. Brasil 2085, Valparaíso, 2362803, Chile
| | - Mónica Kurte
- Laboratory of Cellular and Molecular Immunology, Faculty of Medicine, Universidad de los Andes, Monseñor Álvaro del Portillo N°12.455, Las Condes, Santiago, 750000, Chile
| | - Catalina Fernández-O'Ryan
- Laboratory of Cellular and Molecular Immunology, Faculty of Medicine, Universidad de los Andes, Monseñor Álvaro del Portillo N°12.455, Las Condes, Santiago, 750000, Chile
| | - Melanie Gauthier-Abeliuk
- Laboratory of Cellular and Molecular Immunology, Faculty of Medicine, Universidad de los Andes, Monseñor Álvaro del Portillo N°12.455, Las Condes, Santiago, 750000, Chile
| | - Patricia Fuenzalida
- Laboratory of Cellular and Molecular Immunology, Faculty of Medicine, Universidad de los Andes, Monseñor Álvaro del Portillo N°12.455, Las Condes, Santiago, 750000, Chile
| | - Ivón Moya-Uribe
- Laboratory of Cellular and Molecular Immunology, Faculty of Medicine, Universidad de los Andes, Monseñor Álvaro del Portillo N°12.455, Las Condes, Santiago, 750000, Chile
| | - Claudia Altamirano
- Cell Culture Laboratory Animals, School of of Biochemical Engineering, Pontificia Universidad Católica de Valparaíso, Av. Brasil 2085, Valparaíso, 2362803, Chile
| | - Fernando Figueroa
- Laboratory of Cellular and Molecular Immunology, Faculty of Medicine, Universidad de los Andes, Monseñor Álvaro del Portillo N°12.455, Las Condes, Santiago, 750000, Chile
| | - Carlos Irarrázabal
- Laboratory of Integrative and Molecular Physiology, Faculty of Medicine, Universidad de los Andes, Monseñor Álvaro del Portillo N°12.455, Las Condes, Santiago, 750000, Chile
| | - Flavio Carrión
- Laboratory of Cellular and Molecular Immunology, Faculty of Medicine, Universidad de los Andes, Monseñor Álvaro del Portillo N°12.455, Las Condes, Santiago, 750000, Chile.
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30
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Ma OKF, Chan KH. Immunomodulation by mesenchymal stem cells: Interplay between mesenchymal stem cells and regulatory lymphocytes. World J Stem Cells 2016; 8:268-78. [PMID: 27679683 PMCID: PMC5031888 DOI: 10.4252/wjsc.v8.i9.268] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 07/15/2016] [Accepted: 07/29/2016] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) possess immunomodulatory properties, which confer enormous potential for clinical application. Considerable evidence revealed their efficacy on various animal models of autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus and uveitis. MSCs elicit their immunomodulatory effects by inhibiting lymphocyte activation and proliferation, forbidding the secretion of proinflammatory cytokines, limiting the function of antigen presenting cells, and inducing regulatory T (Treg) and B (Breg) cells. The induction of Treg and Breg cells is of particular interest since Treg and Breg cells have significant roles in maintaining immune tolerance. Several mechanisms have been proposed regarding to the MSCs-mediated induction of Treg and Breg cells. Accordingly, MSCs induce regulatory lymphocytes through secretion of multiple pleiotropic cytokines, cell-to-cell contact with target cells and modulation of antigen-presenting cells. Here, we summarized how MSCs induce Treg and Breg cells to provoke immunosuppression.
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Affiliation(s)
- Oscar Ka-Fai Ma
- Oscar Ka-Fai Ma, Koon Ho Chan, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China
| | - Koon Ho Chan
- Oscar Ka-Fai Ma, Koon Ho Chan, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China
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31
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Özdemir AT, Özgül Özdemir RB, Kırmaz C, Sarıboyacı AE, Ünal Halbutoğlları ZS, Özel C, Karaöz E. The paracrine immunomodulatory interactions between the human dental pulp derived mesenchymal stem cells and CD4 T cell subsets. Cell Immunol 2016; 310:108-115. [PMID: 27576175 DOI: 10.1016/j.cellimm.2016.08.008] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 07/28/2016] [Accepted: 08/20/2016] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) have strong immunomodulatory properties, however these properties may show some differences according to the tissue type of their isolate. In this study we investigated the paracrine interactions between human DP derived MSCs (hDP-MSCs) and the CD4+ T helper cell subsets to establish their immunomodulatory mechanisms. We found that the CD4+-Tbet+ (Th1) and CD4+-Gata3+ (Th2) cells were suppressed by the hDP-MSCs, but the CD4+-Stat3+ (Th17) and CD4+-CD25+-FoxP3+ (Treg) cells were stimulated. The expressions of T cell specific cytokines interferon gamma (IFN-g), interleukin (IL)-4 and IL-17a decreased, but IL-10 and transforming growth factor beta-1 (TGF-b1) increased with the hDP-MSCs. The expressions of indoleamine-pyrrole 2,3-dioxygenase (IDO), prostaglandin E2 (PGE2), soluble human leukocyte antigen G (sHLA-G) derived from hDP-MSCs slightly increased, but hepatocyte growth factor (HGF) significantly increased in the co-culture groups. According to our findings, the hDP-MSCs can suppress the Th1 and Th2 subsets but stimulate the Th17 and Treg subsets. The Stat3 expression of Th17 cells may have been stimulated by the HGF, and thus the pro-inflammatory Th17 cells may have altered into the immunosuppressive regulatory Th17 cells. Further prospective studies are needed to confirm our findings.
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Affiliation(s)
- Alper Tunga Özdemir
- Ege University, Institute of Health Sciences, Department of Stem Cell, 35100 Izmir, Turkey.
| | | | - Cengiz Kırmaz
- Celal Bayar University, Medical School, Department of Internal Medicine, Division of Allergy and Clinical Immunology, 45050 Manisa, Turkey
| | - Ayla Eker Sarıboyacı
- Eskişehir Osmangazi University, Cellular Therapy and Stem Cell Production Application and Research Center, 26480 Eskişehir, Turkey
| | | | - Ceren Özel
- Kocaeli University, Stem Cell and Gene Therapies Research and Application Center, 41000 Kocaeli, Turkey
| | - Erdal Karaöz
- Liv Hospital, Center of Regenerative Medicine and Stem Cell Research, 34000 Istanbul, Turkey; Istinye University, Medical School, Department of Histology and Embryology, 34000 Istanbul, Turkey
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Croes M, Öner FC, van Neerven D, Sabir E, Kruyt MC, Blokhuis TJ, Dhert WJA, Alblas J. Proinflammatory T cells and IL-17 stimulate osteoblast differentiation. Bone 2016; 84:262-270. [PMID: 26780388 DOI: 10.1016/j.bone.2016.01.010] [Citation(s) in RCA: 138] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 01/04/2016] [Accepted: 01/07/2016] [Indexed: 12/15/2022]
Abstract
The local immune response is important to consider when the aim is to improve bone regeneration. Recently T lymphocytes and their associated cytokines have been identified as regulators in fracture callus formation, but it is not known whether T cells affect bone progenitor cells directly. The goal of this in vitro study was to investigate the role of different T cell subsets and their secreted factors on the osteogenic differentiation of human mesenchymal stem cells (MSCs). Significant increases in the alkaline phosphatase activity and the subsequent matrix mineralization by MSCs were found after their exposure to activated T cells or activated T cell-derived conditioned medium. Blocking IFN-γ in the conditioned medium abolished its pro-osteogenic effect, while blocking TGF-β further enhanced osteogenesis. The relative contribution of an anti- or proinflammatory T cell phenotype in MSC osteogenic differentiation was studied next. Enrichment of the fraction of anti-inflammatory regulatory T cells had no beneficial osteogenic effect. In contrast, soluble factors derived from enriched T helper 17 cells upregulated the expression of osteogenic markers by MSCs. IL-17A, and IL-17F, their main proinflammatory cytokines, similarly exhibited strong osteogenic effects when exposed directly to MSCs. IL-17A in particular showed a synergistic action together with bone morphogenetic protein 2. These results indicate that individual T cell subsets, following their activation, affect osteoblast maturation in a different manner through the production of soluble factors. From all T cells, the proinflammatory T cells, including the T helper 17 cells, are most stimulatory for osteogenesis.
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Affiliation(s)
- Michiel Croes
- Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands.
| | - F Cumhur Öner
- Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands.
| | - Danihel van Neerven
- Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands.
| | - Ekrem Sabir
- Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands.
| | - Moyo C Kruyt
- Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands.
| | - Taco J Blokhuis
- Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands.
| | - Wouter J A Dhert
- Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands; Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3508 TD Utrecht, The Netherlands.
| | - Jacqueline Alblas
- Department of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands.
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MicroRNA-27b Enhances the Hepatic Regenerative Properties of Adipose-Derived Mesenchymal Stem Cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2016; 5:e285. [PMID: 26836372 PMCID: PMC4884788 DOI: 10.1038/mtna.2015.55] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Accepted: 11/27/2015] [Indexed: 01/10/2023]
Abstract
Adipose-derived mesenchymal stem cells (ASCs) are readily available multipotent mesenchymal progenitor cells and have become an attractive therapeutic tool for regenerative medicine. We herein investigated the mechanistic role of how miR-27b modulated regenerative capacities of ASCs. Intravenous administration of miR-27b-transfected ASCs (ASCs-miR-27b) was conducted after 70% partial hepatectomy (PH). After PH, rats injected with ASCs-miR-27b had decreased inflammatory cytokines and increased hepatocyte growth factor and other related growth factors. We showed that the nature of ASCs-miR-27b to inhibit hepatic stellate cell activation was dependent upon peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in vitro. Moreover, expression of miR-27b in ASCs induced heme oxygenase-1 (HO-1), resulting in increased production of ATP, protective cytokines/growth factors, and genes involved in mitochondrial biogenesis in a PGC-1α-dependent manner. RNA sequencing (RNA-Seq) analysis revealed drastic transcriptional changes in livers treated with ASCs-miR-27b after PH. The differentially expressed genes classified into "regeneration," "fibrosis," and "mitochondrial biogenesis" clusters were mainly mitochondrial. The potential biological context reflecting the effects of PGC-1α by ASCs-miR-27b treatment was also observed by the subnetwork analysis with HO-1 and PGC-1α being the top-ranked regulatory genes. We demonstrate autologous ASCs-miR-27b enhances liver regeneration and, importantly, preserves hepatic function through paracrine actions which offers a viable therapeutic option to facilitate rapid recovery after liver injury.
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Mattar P, Bieback K. Comparing the Immunomodulatory Properties of Bone Marrow, Adipose Tissue, and Birth-Associated Tissue Mesenchymal Stromal Cells. Front Immunol 2015; 6:560. [PMID: 26579133 PMCID: PMC4630659 DOI: 10.3389/fimmu.2015.00560] [Citation(s) in RCA: 202] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 10/19/2015] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSC) have gained immense attraction in regenerative medicine, tissue engineering, and immunotherapy. This is based on their differentiation potential and the supply of pro-regenerative and immunomodulatory signals. MSC can be isolated from a multitude of tissue sources, but mainly bone marrow, adipose tissue, and birth-associated tissues (e.g., umbilical cord, cord blood, placenta) appear to be relevant for clinical translation in immune-mediated disorders. However, only a few studies directly compared the immunomodulatory potency of MSC from different tissue sources. This review compiles the current literature regarding the similarities and differences between these three sources for MSCs with a special focus on their immunomodulatory effects on T-lymphocyte subsets and monocytes, macrophages, and dendritic cells.
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Affiliation(s)
- Philipp Mattar
- Stem Cell Laboratory, Medical Faculty Mannheim, Institute of Transfusion Medicine and Immunology, Heidelberg University , Heidelberg , Germany ; German Red Cross Blood Service Baden-Württemberg - Hessen , Mannheim , Germany
| | - Karen Bieback
- Stem Cell Laboratory, Medical Faculty Mannheim, Institute of Transfusion Medicine and Immunology, Heidelberg University , Heidelberg , Germany ; German Red Cross Blood Service Baden-Württemberg - Hessen , Mannheim , Germany
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The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus. Cell Mol Immunol 2015; 14:423-431. [PMID: 26435067 DOI: 10.1038/cmi.2015.89] [Citation(s) in RCA: 178] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Revised: 08/01/2015] [Accepted: 08/26/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown immunoregulation of various immune cells. The aim of this study was to investigate the mechanism of UC MSCs in the regulation of peripheral regulatory T cells (Treg) and T helper 17 (Th17) cells in patients with systemic lupus erythematosus (SLE). METHODS Thirty patients with active SLE, refractory to conventional therapies, were given UC MSCs infusions. The percentages of peripheral blood CD4+CD25+Foxp3+ regulatory T cells (Treg) and CD3+CD8-IL17A+ Th17 cells and the mean fluorescence intensities (MFI) of Foxp3 and IL-17 were measured at 1 week, 1 month, 3 months, 6 months, and 12 months after MSCs transplantation (MSCT). Serum cytokines, including transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-17A were detected using ELISA. Peripheral blood mononuclear cells from patients were collected and co-cultured with UC MSCs at ratios of 1:1, 10:1, and 50:1, respectively, for 72 h to detect the proportions of Treg and Th17 cells and the MFIs of Foxp3 and IL-17 were determined by flow cytometry. The cytokines in the supernatant solution were detected using ELISA. Inhibitors targeting TGF-β, IL-6, indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 were added to the co-culture system, and the percentages of Treg and Th17 cells were observed. RESULTS The percentage of peripheral Treg and Foxp3 MFI increased 1 week, 1 month, and 3 months after UC MSCs transplantation, while the Th17 proportion and MFI of IL-17 decreased 3 months, 6 months, and 12 months after the treatment, along with an increase in serum TGF-β at 1 week, 3 months, and 12 months and a decrease in serum TNF-α beginning at 1 week. There were no alterations in serums IL-6 and IL-17A before or after MSCT. In vitro studies showed that the UC MSCs dose-dependently up-regulated peripheral Treg proportion in SLE patients, which was not depended on cell-cell contact. However, the down-regulation of Th17 cells was not dose-dependently and also not depended on cell-cell contact. Supernatant TGF-β and IL-6 levels significantly increased, TNF-α significantly decreased, but IL-17A had no change after the co-culture. The addition of anti-TGF-β antibody significantly abrogated the up-regulation of Treg, and the addition of PGE2 inhibitor significantly abrogated the down-regulation of Th17 cells. Both anti-IL-6 antibody and IDO inhibitor had no effects on Treg and Th17 cells. CONCLUSIONS UC MSCs up-regulate Treg and down-regulate Th17 cells through the regulation of TGF-β and PGE2 in lupus patients.
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Rosado MM, Bernardo ME, Scarsella M, Conforti A, Giorda E, Biagini S, Cascioli S, Rossi F, Guzzo I, Vivarelli M, Dello Strologo L, Emma F, Locatelli F, Carsetti R. Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. Stem Cells Dev 2015; 24:93-103. [PMID: 25036865 DOI: 10.1089/scd.2014.0155] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Bone marrow (BM)-derived mesenchymal stromal cells (MSCs), endowed with immunosuppressive and anti-inflammatory properties, represent a promising tool in immunoregulatory and regenerative cell therapy. Clarifying the interactions between MSCs and B-lymphocytes may be crucial for designing innovative MSC-based strategies in conditions in which B cells play a role, including systemic lupus erythematosus (SLE) and rejection of kidney transplantation. In this study, we show that, both in healthy subjects and in patients, in vitro B-cell proliferation, plasma-cell differentiation, and antibody production are inhibited by BM-derived MSCs when peripheral blood lymphocytes are stimulated with CpG, but not when sorted B cells are cultured with MSCs+CpG. Inhibition is restored in CpG+MSC cocultures when sorted T cells are added to sorted B cells, suggesting that this effect is mediated by T cells, with both CD4(+) and CD8(+) cells playing a role. Moreover, cell-cell contact between MSCs and T cells, but not between MSCs and B cells, is necessary to inhibit B-cell proliferation. Thus, the presence of functional T cells, as well as cell-cell contact between MSCs and T cells, are crucial for B-cell inhibition. This information can be relevant for implementing MSC-based therapeutic immune modulation in patients in whom T-cell function is impaired.
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Affiliation(s)
- Maria Manuela Rosado
- 1 Immunology Research Area, Ospedale Pediatrico Bambino Gesù, IRCSS , Roma, Italy
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Umbilical cord blood-derived mesenchymal stem cells ameliorate graft-versus-host disease following allogeneic hematopoietic stem cell transplantation through multiple immunoregulations. ACTA ACUST UNITED AC 2015. [DOI: 10.1007/s11596-015-1456-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Mesenchymal Stromal Cell Therapy in Ischemia/Reperfusion Injury. J Immunol Res 2015; 2015:602597. [PMID: 26258151 PMCID: PMC4518154 DOI: 10.1155/2015/602597] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 06/07/2015] [Indexed: 12/24/2022] Open
Abstract
Ischemia/reperfusion injury (IRI) represents a worldwide public health issue of increasing incidence. IRI may virtually affect all organs and tissues and is associated with significant morbidity and mortality. Particularly, the duration of blood supply deprivation has been recognized as a critical factor in stroke, hemorrhagic shock, or myocardial infarction, as well as in solid organ transplantation (SOT). Pathophysiologically, IRI causes multiple cellular and tissular metabolic and architectural changes. Furthermore, the reperfusion of ischemic tissues induces both local and systemic inflammation. In the particular field of SOT, IRI is an unavoidable event, which conditions both short- and long-term outcomes of graft function and survival. Clinically, the treatment of patients with IRI mostly relies on supportive maneuvers since no specific target-oriented therapy has been validated thus far. In the present review, we summarize the current literature on mesenchymal stromal cells (MSC) and their potential use as cell therapy in IRI. MSC have demonstrated immunomodulatory, anti-inflammatory, and tissue repair properties in rodent studies and in preliminary clinical trials, which may open novel avenues in the management of IRI and SOT.
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Cao W, Cao K, Cao J, Wang Y, Shi Y. Mesenchymal stem cells and adaptive immune responses. Immunol Lett 2015; 168:147-53. [PMID: 26073566 DOI: 10.1016/j.imlet.2015.06.003] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 06/04/2015] [Indexed: 12/12/2022]
Abstract
Over the past decade, our understanding of the regulatory role of mesenchymal stem cells (MSCs) in adaptive immune responses through both preclinical and clinical studies has dramatically expanded, providing great promise for treating various inflammatory diseases. Most studies are focused on the modulatory effects of these cells on the properties of T cell-mediated immune responses, including activation, proliferation, survival, and subset differentiation. Interestingly, the immunosuppressive function of MSCs was found to be licensed by IFN-γ and TNF-α produced by T cells and that can be further amplified by cytokines such as IL-17. However, the immunosuppressive function of MSCs can be reversed in certain situation, such as suboptimal levels of inflammatory cytokines, or in the presence of immunosuppressive molecules. Here we review the influence of MSCs on adaptive immune system, especially their bidirectional interaction in tuning the immune microenvironment and subsequently repairing damaged tissue. Understanding MSC-mediated regulation of T cells is expected to provide fundamental information for guiding appropriate applications of MSCs in clinical settings.
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Affiliation(s)
- Wei Cao
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Kai Cao
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Jianchang Cao
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Ying Wang
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Yufang Shi
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, 199 Renai Road, Suzhou 215123, China.
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Tan W, Gu Z, Shen B, Jiang J, Meng Y, Da Z, Liu H, Tao T, Cheng C. PTEN/Akt-p27kip1Signaling Promote the BM-MSCs Senescence and Apoptosis in SLE Patients. J Cell Biochem 2015; 116:1583-94. [PMID: 25649549 DOI: 10.1002/jcb.25112] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 01/23/2015] [Indexed: 01/18/2023]
Affiliation(s)
- Wei Tan
- Department of Rheumatology; Affiliated Hospital of Nantong University; Nantong 226001 China
- Department of Emergency; The Yangzhou First People's Hospital; Yangzhou 225001 China
| | - Zhifeng Gu
- Department of Rheumatology; Affiliated Hospital of Nantong University; Nantong 226001 China
| | - Biyu Shen
- Department of Rheumatology; Affiliated Hospital of Nantong University; Nantong 226001 China
| | - Jinxia Jiang
- Department of Rheumatology; Affiliated Hospital of Nantong University; Nantong 226001 China
| | - Yan Meng
- Department of Rheumatology; Affiliated Hospital of Nantong University; Nantong 226001 China
| | - Zhanyun Da
- Department of Rheumatology; Affiliated Hospital of Nantong University; Nantong 226001 China
| | - Hong Liu
- Department of Immunology; Medical College; Nantong University; Nantong 226001 China
| | - Tao Tao
- Department of Immunology; Medical College; Nantong University; Nantong 226001 China
| | - Chun Cheng
- Department of Immunology; Medical College; Nantong University; Nantong 226001 China
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target; Medical College; Nantong University; Nantong 226001 China
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Human Bone Marrow-Derived Mesenchymal Stromal Cells Differentially Inhibit Cytokine Production by Peripheral Blood Monocytes Subpopulations and Myeloid Dendritic Cells. Stem Cells Int 2015; 2015:819084. [PMID: 26060498 PMCID: PMC4427776 DOI: 10.1155/2015/819084] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 04/05/2015] [Indexed: 12/17/2022] Open
Abstract
The immunosuppressive properties of mesenchymal stromal/stem cells (MSC) rendered them an attractive therapeutic approach for immune disorders and an increasing body of evidence demonstrated their clinical value. However, the influence of MSC on the function of specific immune cell populations, namely, monocyte subpopulations, is not well elucidated. Here, we investigated the influence of human bone marrow MSC on the cytokine and chemokine expression by peripheral blood classical, intermediate and nonclassical monocytes, and myeloid dendritic cells (mDC), stimulated with lipopolysaccharide plus interferon (IFN)γ. We found that MSC effectively inhibit tumor necrosis factor- (TNF-) α and macrophage inflammatory protein- (MIP-) 1β protein expression in monocytes and mDC, without suppressing CCR7 and CD83 protein expression. Interestingly, mDC exhibited the highest degree of inhibition, for both TNF-α and MIP-1β, whereas the reduction of TNF-α expression was less marked for nonclassical monocytes. Similarly, MSC decreased mRNA levels of interleukin- (IL-) 1β and IL-6 in classical monocytes, CCL3, CCL5, CXCL9, and CXCL10 in classical and nonclassical monocytes, and IL-1β and CXCL10 in mDC. MSC do not impair the expression of maturation markers in monocytes and mDC under our experimental conditions; nevertheless, they hamper the proinflammatory function of monocytes and mDC, which may impede the development of inflammatory immune responses.
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Wada N, Gronthos S, Bartold PM. Immunomodulatory effects of stem cells. Periodontol 2000 2015; 63:198-216. [PMID: 23931061 DOI: 10.1111/prd.12024] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2012] [Indexed: 02/06/2023]
Abstract
Adult-derived mesenchymal stem cells have received considerable attention over the past two decades for their potential use in tissue engineering, principally because of their potential to differentiate into multiple stromal-cell lineages. Recently, the immunomodulatory properties of mesenchymal stem cells have attracted interest as a unique property of these cells that may be harnessed for novel therapeutic approaches in immune-mediated diseases. Mesenchymal stem cells have been shown to inhibit the proliferation of activated T-cells both in vitro and in vivo but to stimulate T-regulatory cell proliferation. Mesenchymal stem cells are also known to be weakly immunogenic and to exert immunosuppressive effects on B-cells, natural killer cells, dendritic cells and neutrophils through various mechanisms. Furthermore, intravenous administration of allogeneic mesenchymal stem cells has shown a marked suppression of host immune reactions in preclinical animal models of large-organ transplant rejection and in various autoimmune- and inflammatory-based diseases. Some clinical trials utilizing human mesenchymal stem cells have also produced promising outcomes in patients with graft-vs.-host disease and autoimmune diseases. Mesenchymal stem cells identified from various dental tissues, including periodontal ligament stem cells, also possess multipotent and immunomodulatory properties. Hence, dental mesenchymal stem cells may represent an alternate cell source, not only for tissue regeneration but also as therapies for autoimmune- and inflammatory-mediated diseases. These findings have elicited interest in dental tissue mesenchymal stem cells as alternative cell sources for modulating alloreactivity during tissue regeneration following transplantation into human leukocyte antigen-mismatched donors. To examine this potential in periodontal regeneration, future work will need to assess the capacity of allogeneic periodontal ligament stem cells to regenerate periodontal ligament in animal models of periodontal disease. The present review describes the immunosuppressive effects of mesenchymal stem cells on various types of immune cells, the potential mechanisms through which they exert their mode of action and the preclinical animal studies and human clinical trials that have utilized mesenchymal stem cells, including those populations originating from dental structures.
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Intravenous administration of bone marrow-derived mesenchymal stem cells induces a switch from classical to atypical symptoms in experimental autoimmune encephalomyelitis. Stem Cells Int 2015; 2015:140170. [PMID: 25838828 PMCID: PMC4369963 DOI: 10.1155/2015/140170] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 01/23/2015] [Accepted: 01/23/2015] [Indexed: 01/01/2023] Open
Abstract
Potent immunosuppressive and regenerative properties of mesenchymal stem cells (MSCs) position them as a novel therapy for autoimmune diseases. This research examines the therapeutic effect of MSCs administration at different disease stages in experimental autoimmune encephalomyelitis (EAE). Classical and atypical scores of EAE, associated with Th1 and Th17 response, respectively, and also Treg lymphocytes, were evaluated. MSCs administration at the onset (EAE+MSConset) induced an important amelioration of the clinical signs and less lasting effect at the peak of EAE (EAE+MSCpeak). No effect was observed when MSCs were applied after EAE stabilization (EAE+MSClate). Surprisingly, EAE atypical signs were detected in EAE+MSCpeak and EAE+MSClate mice. However, no correlation was found in Th17/Th1 ratio. Interestingly, regardless of time administration, MSCs significantly reduced IL-6 and also T-bet, RORγT, and Foxp3 mRNA levels in brain samples of EAE mice. The downregulation of IL-6 could restore the well-functioning of the blood-brain barrier of EAE mice, correlated with a decreased number of brain infiltrating leukocytes. These results suggest that the inflammatory status is important to be considered for administering MSCs in autoimmune pathologies, leading to a further research to clarify the effect of MSCs for multiple sclerosis.
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André T, Najar M, Stamatopoulos B, Pieters K, Pradier O, Bron D, Meuleman N, Lagneaux L. Immune impairments in multiple myeloma bone marrow mesenchymal stromal cells. Cancer Immunol Immunother 2015; 64:213-24. [PMID: 25341809 PMCID: PMC11029797 DOI: 10.1007/s00262-014-1623-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 10/04/2014] [Indexed: 10/25/2022]
Abstract
In multiple myeloma (MM), bone marrow mesenchymal stromal cells (BM-MSCs) play an important role in pathogenesis and disease progression by supporting myeloma cell growth and immune escape. Previous studies have suggested that direct and indirect interactions between malignant cells and BM-MSCs result in constitutive abnormal immunomodulatory capacities in MM BM-MSCs. The aim of this study was to investigate the mechanisms that underlie these MM BM-MSCs abnormalities. We demonstrated that MM BM-MSCs exhibit abnormal expression of CD40/40L, VCAM1, ICAM-1, LFA-3, HO-1, HLA-DR and HLA-ABC. Furthermore, an overproduction of IL-6 (1,806 ± 152.5 vs 719.6 ± 18.22 ng/mL; p = 0.035) and a reduced secretion of IL-10 (136 ± 15.02 vs 346.4 ± 35.32 ng/mL; p = 0.015) were quantified in culture medium when MM BM-MSCs were co-cultured with T lymphocytes compared to co-cultures with healthy donor (HD) BM-MSCs. An increased Th17/Treg ratio was observed when T cells were co-cultured with MM BM-MSCs compared to co-cultures with HD BM-MSCs (0.955 vs 0.055). Together, these observations demonstrated that altered immunomodulation capacities of MM BM-MSCs were linked to variations in their immunogenicity and secretion profile. These alterations lead not only to a reduced inhibition of T cell proliferation but also to a shift in the Th17/Treg balance. We identified factors that are potentially responsible for these alterations, such as IL-6, VCAM-1 and CD40, which could also be associated with MM pathogenesis and progression.
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Affiliation(s)
- Thibaud André
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet - Université Libre de Bruxelles (ULB), 808, Route de Lennik, 1070, Brussels, Belgium,
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Effect of human bone marrow mesenchymal stromal cells on cytokine production by peripheral blood naive, memory, and effector T cells. Stem Cell Res Ther 2015; 6:3. [PMID: 25559824 PMCID: PMC4417198 DOI: 10.1186/scrt537] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 12/12/2014] [Accepted: 12/15/2014] [Indexed: 12/14/2022] Open
Abstract
Introduction The different distribution of T cells among activation/differentiation stages in immune disorders may condition the outcome of mesenchymal stromal cell (MSC)-based therapies. Indeed, the effect of MSCs in the different functional compartments of T cells is not completely elucidated. Methods We investigated the effect of human bone marrow MSCs on naturally occurring peripheral blood functional compartments of CD4+ and CD8+ T cells: naive, central memory, effector memory, and effector compartments. For that, mononuclear cells (MNCs) stimulated with phorbol myristate acetate (PMA) plus ionomycin were cultured in the absence/presence of MSCs. The percentage of cells expressing tumor necrosis factor-alpha (TNF-α), interferon gamma (IFNγ), and interleukin-2 (IL-2), IL-17, IL-9, and IL-6 and the amount of cytokine produced were assessed by flow cytometry. mRNA levels of IL-4, IL-10, transforming growth factor-beta (TGF-β), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) in purified CD4+ and CD8+ T cells, and phenotypic and mRNA expression changes induced by PMA + ionomycin stimulation in MSCs, were also evaluated. Results MSCs induced the reduction of the percentage of CD4+ and CD8+ T cells producing TNF-α, IFNγ, and IL-2 in all functional compartments, except for naive IFNγ+CD4+ T cells. This inhibitory effect differentially affected CD4+ and CD8+ T cells as well as the T-cell functional compartments; remarkably, different cytokines showed distinct patterns of inhibition regarding both the percentage of producing cells and the amount of cytokine produced. Likewise, the percentages of IL-17+, IL-17+TNF-α+, and IL-9+ within CD4+ and CD8+ T cells and of IL-6+CD4+ T cells were decreased in MNC-MSC co-cultures. MSCs decreased IL-10 and increased IL-4 mRNA expression in stimulated CD4+ and CD8+ T cells, whereas TGF-β was reduced in CD8+ and augmented in CD4+ T cells, with no changes for CTLA4. Finally, PMA + ionomycin stimulation did not induce significant alterations on MSCs phenotype but did increase indoleamine-2,3-dioxygenase (IDO), inducible costimulatory ligand (ICOSL), IL-1β, IL-8, and TNF-α mRNA expression. Conclusions Overall, our study showed that MSCs differentially regulate the functional compartments of CD4+ and CD8+ T cells, which may differentially impact their therapeutic effect in immune disorders. Furthermore, the influence of MSCs on IL-9 expression can open new possibilities for MSC-based therapy in allergic diseases. Electronic supplementary material The online version of this article (doi:10.1186/scrt537) contains supplementary material, which is available to authorized users.
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Singh RP, Hasan S, Sharma S, Nagra S, Yamaguchi DT, Wong DTW, Hahn BH, Hossain A. Th17 cells in inflammation and autoimmunity. Autoimmun Rev 2014; 13:1174-81. [PMID: 25151974 DOI: 10.1016/j.autrev.2014.08.019] [Citation(s) in RCA: 169] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 07/05/2014] [Indexed: 02/06/2023]
Abstract
T helper 17 (Th17), a distinct subset of CD4(+) T cells with IL-17 as their major cytokine, orchestrate the pathogenesis of inflammatory and autoimmune diseases. Dysregulated Th17 cells contribute to inflammatory and autoimmune diseases. Candidate biologics are in development for targeting IL-17, IL-17 receptors or IL-17 pathways. Several drugs that impact the IL-17 pathway are already in clinical trials for the treatment of autoimmune diseases. In this review we provide evidence for the role of Th17 cells in immune-mediated diseases. An understanding of the role of Th17 in these conditions will provide important insights and unravel novel targets for therapeutic intervention.
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Affiliation(s)
- Ram Pyare Singh
- Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-1670, USA; Research Service, Veterans Affairs Greater Los Angeles Health Care System, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-1670, USA.
| | - Sascha Hasan
- Sanguine Biosciences Inc, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-1670, USA
| | - Sherven Sharma
- Research Service, Veterans Affairs Greater Los Angeles Health Care System, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-1670, USA
| | - Saranpreet Nagra
- Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-1670, USA
| | - Dean T Yamaguchi
- Research Service, Veterans Affairs Greater Los Angeles Health Care System, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-1670, USA
| | - David T W Wong
- UCLA School of Dentistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-1670, USA
| | - Bevra H Hahn
- Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-1670, USA
| | - Awlad Hossain
- Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-1670, USA
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Wang X, Kimbrel EA, Ijichi K, Paul D, Lazorchak AS, Chu J, Kouris NA, Yavanian GJ, Lu SJ, Pachter JS, Crocker SJ, Lanza R, Xu RH. Human ESC-derived MSCs outperform bone marrow MSCs in the treatment of an EAE model of multiple sclerosis. Stem Cell Reports 2014; 3:115-30. [PMID: 25068126 PMCID: PMC4110787 DOI: 10.1016/j.stemcr.2014.04.020] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 04/24/2014] [Accepted: 04/29/2014] [Indexed: 02/09/2023] Open
Abstract
Current therapies for multiple sclerosis (MS) are largely palliative, not curative. Mesenchymal stem cells (MSCs) harbor regenerative and immunosuppressive functions, indicating a potential therapy for MS, yet the variability and low potency of MSCs from adult sources hinder their therapeutic potential. MSCs derived from human embryonic stem cells (hES-MSCs) may be better suited for clinical treatment of MS because of their unlimited and stable supply. Here, we show that hES-MSCs significantly reduce clinical symptoms and prevent neuronal demyelination in a mouse experimental autoimmune encephalitis (EAE) model of MS, and that the EAE disease-modifying effect of hES-MSCs is significantly greater than that of human bone-marrow-derived MSCs (BM-MSCs). Our evidence also suggests that increased IL-6 expression by BM-MSCs contributes to the reduced anti-EAE therapeutic activity of these cells. A distinct ability to extravasate and migrate into inflamed CNS tissues may also be associated with the robust therapeutic effects of hES-MSCs on EAE.
hES-MSCs show increased anti-EAE effects relative to adult human BM-MSCs hES-MSCs express fewer proinflammatory cytokines than BM-MSCs hES-MSCs enter the CNS more efficiently than BM-MSCs in EAE
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Affiliation(s)
- Xiaofang Wang
- Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030, USA ; ImStem Biotechnology, Inc., 400 Farmington Avenue, Farmington, CT 06030, USA
| | - Erin A Kimbrel
- Advanced Cell Technology, 33 Locke Drive, Marlborough, MA 01752, USA
| | - Kumiko Ijichi
- Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Debayon Paul
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Adam S Lazorchak
- ImStem Biotechnology, Inc., 400 Farmington Avenue, Farmington, CT 06030, USA
| | - Jianlin Chu
- Advanced Cell Technology, 33 Locke Drive, Marlborough, MA 01752, USA
| | - Nicholas A Kouris
- Advanced Cell Technology, 33 Locke Drive, Marlborough, MA 01752, USA
| | | | - Shi-Jiang Lu
- Advanced Cell Technology, 33 Locke Drive, Marlborough, MA 01752, USA
| | - Joel S Pachter
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Stephen J Crocker
- Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Robert Lanza
- Advanced Cell Technology, 33 Locke Drive, Marlborough, MA 01752, USA
| | - Ren-He Xu
- Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030, USA ; ImStem Biotechnology, Inc., 400 Farmington Avenue, Farmington, CT 06030, USA ; Faculty of Health Sciences, University of Macau, Taipa, Macau, China
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Khoury M, Alcayaga-Miranda F, Illanes SE, Figueroa FE. The promising potential of menstrual stem cells for antenatal diagnosis and cell therapy. Front Immunol 2014; 5:205. [PMID: 24904569 PMCID: PMC4032935 DOI: 10.3389/fimmu.2014.00205] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 04/25/2014] [Indexed: 12/21/2022] Open
Abstract
Menstrual-derived stem cells (MenSCs) are a new source of mesenchymal stem cells isolated from the menstrual fluid. Currently, there is a growing interest in their clinical potential due to fact that they are multipotent, highly proliferative, and easy to obtain in a non-invasive manner. Sampling can be repeated periodically in a simplified and reproducible manner devoid of complications that no existing cell source can match. MenSCs are also free of ethical dilemmas, and display novel properties with regard to presently known adult derived stem cells. This review details their distinctive biological properties regarding immunophenotype and function, proliferation rate, differentiation potential, and paracrine effects mediated by secreted factors. Their possible role in antenatal diagnosis is also discussed. While more insight on their immunomodulatory and diagnostic properties is needed, the impact of clinical and epidemiological factors, such as age, use of contraceptives, or hormonal status still requires further investigations to properly assess their current and future use in clinical application and diagnosis.
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Affiliation(s)
- Maroun Khoury
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes , Santiago , Chile ; Cells for Cells , Santiago , Chile ; REGENERO, Consortium in Tissue Engineering , Santiago , Chile
| | - Francisca Alcayaga-Miranda
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes , Santiago , Chile ; Cells for Cells , Santiago , Chile
| | - Sebastián E Illanes
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes , Santiago , Chile
| | - Fernando E Figueroa
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes , Santiago , Chile
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Figueroa FE, Cuenca Moreno J, La Cava A. Novel approaches to lupus drug discovery using stem cell therapy. Role of mesenchymal-stem-cell-secreted factors. Expert Opin Drug Discov 2014; 9:555-66. [PMID: 24655067 DOI: 10.1517/17460441.2014.897692] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Patients with systemic lupus erythematosus (SLE) are at increased risk for premature death, particularly among young adults, and present dilemmas regarding drug efficacy versus toxicity. Novel therapeutic strategies have included the use of mesenchymal stem cell (MSC) therapies that are promising but still have limitations. In several disease models, it has become apparent that MSCs do not necessarily replace diseased tissues but rather exert complex paracrine effects that are mediated by their extracellular-secreted products. AREAS COVERED In this review, the authors highlight the data on MSC treatment of SLE and related mechanisms of actions. This data includes the recent evidence that MSC-secreted factors such as extracellular microvesicles (MVs) are important mediators of MSC therapy. Among MVs, the authors delineate the role of exosomes as triggers of regenerative effects in target cells, mediated by transfer of proteins, mRNAs or microRNAs. The authors also outline some of the biological and regulatory restraints encountered by MSC therapy, in contrast to the potential advantages of MSC-derived exosomes as new therapeutic tools in SLE. EXPERT OPINION There is concern about reproducible data on the use of MSC therapy in rheumatic diseases and specifically SLE. Although most experts consider MSCs to be safe, there are still worries over donor variability, immune-mediated rejection, culture-induced senescence, loss of functional properties and genetic instability or eventual malignant transformation. MSC-released factors could avoid most limiting factors associated with cell therapy and are therefore expected to provide a new and safe therapeutic option at an affordable cost.
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Affiliation(s)
- Fernando E Figueroa
- Universidad de los Andes, Centro de Investigaciones Biomédicas, Facultad de Medicina , Santiago de , Chile
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50
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Erpicum P, Detry O, Weekers L, Bonvoisin C, Lechanteur C, Briquet A, Beguin Y, Krzesinski JM, Jouret F. Mesenchymal stromal cell therapy in conditions of renal ischaemia/reperfusion. Nephrol Dial Transplant 2014; 29:1487-93. [PMID: 24516234 DOI: 10.1093/ndt/gft538] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Acute kidney injury (AKI) represents a worldwide public health issue of increasing incidence, with a significant morbi-mortality. AKI treatment mostly relies on supportive manoeuvres in the absence of specific target-oriented therapy. The pathophysiology of AKI commonly involves ischaemia/reperfusion (I/R) events, which cause both immune and metabolic consequences in renal tissue. Similarly, at the time of kidney transplantation (KT), I/R is an unavoidable event which contributes to early graft dysfunction and enhanced graft immunogenicity. Mesenchymal stromal cells (MSCs) represent a heterogeneous population of adult, fibroblast-like multi-potent cells characterized by their ability to differentiate into tissues of mesodermal lineages. Because MSC have demonstrated immunomodulatory, anti-inflammatory and tissue repair properties, MSC administration at the time of I/R and/or at later times has been hypothesized to attenuate AKI severity and to accelerate the regeneration process. Furthermore, MSC in KT could help prevent both I/R injury and acute rejection, thereby increasing graft function and survival. In this review, summarizing the encouraging observations in animal models and in pilot clinical trials, we outline the benefit of MSC therapy in AKI and KT, and envisage their putative role in renal ischaemic conditioning.
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Affiliation(s)
- Pauline Erpicum
- Divisions of Nephrology and Transplantation, University of Liege CHU (ULg CHU), Liege, Belgium
| | - Olivier Detry
- Abdominal Surgery and Transplantation, University of Liege CHU (ULg CHU), Liege, Belgium Laboratories of Cardiovascular Sciences, University of Liege, Liege, Belgium
| | - Laurent Weekers
- Divisions of Nephrology and Transplantation, University of Liege CHU (ULg CHU), Liege, Belgium
| | - Catherine Bonvoisin
- Divisions of Nephrology and Transplantation, University of Liege CHU (ULg CHU), Liege, Belgium
| | - Chantal Lechanteur
- Laboratory of Cell and Gene Therapy, University of Liege CHU (ULg CHU), Liege, Belgium
| | - Alexandra Briquet
- Laboratory of Cell and Gene Therapy, University of Liege CHU (ULg CHU), Liege, Belgium Hematology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), University of Liege, Liege, Belgium
| | - Yves Beguin
- Laboratory of Cell and Gene Therapy, University of Liege CHU (ULg CHU), Liege, Belgium Hematology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), University of Liege, Liege, Belgium
| | - Jean-Marie Krzesinski
- Divisions of Nephrology and Transplantation, University of Liege CHU (ULg CHU), Liege, Belgium Laboratories of Cardiovascular Sciences, University of Liege, Liege, Belgium
| | - François Jouret
- Divisions of Nephrology and Transplantation, University of Liege CHU (ULg CHU), Liege, Belgium Laboratories of Cardiovascular Sciences, University of Liege, Liege, Belgium
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