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1
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Lu W, Allickson J. Mesenchymal stromal cell therapy: Progress to date and future outlook. Mol Ther 2025:S1525-0016(25)00093-0. [PMID: 39916329 DOI: 10.1016/j.ymthe.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/16/2025] [Accepted: 02/03/2025] [Indexed: 02/28/2025] Open
Abstract
In clinical trials, mesenchymal stromal/stem cells (MSCs) have consistently demonstrated safety. However, demonstration of efficacy has been inconsistent and many MSC trials have failed to meet their efficacy endpoint. This disappointing reality is reflected by the limited number MSC therapies approved by regulatory agencies, despite the large number of MSC trials registered on clinicaltrials.gov. Notably, there has been a recent approval of an MSC therapy for pediatric graft-vs.-host disease in the United States, marking the first MSC therapy approved by the U.S. Food and Drug Administration. This review provides a background of the history and potential therapeutic value of MSCs, an overview of MSC products with regulatory approval, and a summary of registered MSC trials. It concludes with a discussion on current and ongoing challenges and questions surrounding MSC therapy that remains to be resolved before becoming available for routine clinical use outside of clinical trials.
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Affiliation(s)
- Wen Lu
- Department of Laboratory Medicine and Pathology, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN, USA.
| | - Julie Allickson
- Department of Laboratory Medicine and Pathology, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN, USA
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2
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Zeiser R, Ringden O, Sadeghi B, Gonen-Yaacovi G, Segurado OG. Novel therapies for graft versus host disease with a focus on cell therapies. Front Immunol 2023; 14:1241068. [PMID: 37868964 PMCID: PMC10585098 DOI: 10.3389/fimmu.2023.1241068] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 09/11/2023] [Indexed: 10/24/2023] Open
Abstract
Graft versus host disease (GVHD) can occur at any period post allogeneic hematopoietic stem cell transplantation as a common clinical complication contributing to significant morbidity and mortality. Acute GVHD develops in approximately 30-50% of patients receiving transplants from matched related donors. High doses of steroids are used as first-line treatment, but are unsuccessful in around 40% of patients, resulting in the diagnosis of steroid-refractory acute GVHD. Consensus has yet to develop for the management of steroid-refractory acute GVHD, and prognosis at six months has been estimated at around 50%. Thus, it is critical to find effective treatments that increase survival of steroid-refractory acute GVHD. This article describes the currently known characteristics, pathophysiology, and treatments for GVHD, with a special focus on recent advances in cell therapies. In particular, a novel cell therapy using decidua stromal cells (DSCs) was recently shown to have promising results for acute GVHD, with improved effectiveness over previous treatments including mesenchymal stromal cells. At the Karolinska Institute, severe acute GVHD patients treated with placenta-derived DSCs supplemented with either 5% albumin or 10% AB plasma displayed a one-year survival rate of 76% and 47% respectively. Furthermore, patients with steroid-refractory acute GVHD, displayed survival rates of 73% with albumin and 31% with AB plasma-supplemented DSCs, compared to the 20% survival rate in the mesenchymal stromal cell control group. Adverse events and deaths were found to be attributed only to complications of hematopoietic stem cell transplant and GVHD, not to the study intervention. ASC Therapeutics, Inc, in collaboration with the Karolinska Institute, will soon initiate a phase 2 multicenter, open-label study to further assess the efficacy and safety of intravenous DSC treatment in sixty patients with Grade II-IV steroid-refractory acute GVHD. This novel cell therapy represents a promising treatment to combat the poor prognosis that steroid-refractory acute GVHD patients currently face.
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Affiliation(s)
- Robert Zeiser
- Department of Medicine at the University of Freiburg, Freiburg, Germany
| | - Olle Ringden
- Department of Clinical Sciences, Karolinska Institute, Stockholm, Sweden
| | - Behnam Sadeghi
- Department of Clinical Sciences, Karolinska Institute, Stockholm, Sweden
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3
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Kadri N, Amu S, Iacobaeus E, Boberg E, Le Blanc K. Current perspectives on mesenchymal stromal cell therapy for graft versus host disease. Cell Mol Immunol 2023; 20:613-625. [PMID: 37165014 DOI: 10.1038/s41423-023-01022-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 04/07/2023] [Indexed: 05/12/2023] Open
Abstract
Graft versus host disease (GvHD) is the clinical condition in which bone marrow-derived mesenchymal stromal cells (MSCs) have been most frequently studied. In this review, we summarize the experience from clinical trials that have paved the way to translation. While MSC-based therapy has shown an exceptional safety profile, identifying potency assays and disease biomarkers that reliably predict the capacity of a specific MSC batch to alleviate GvHD has been difficult. As GvHD diagnosis and staging are based solely on clinical criteria, individual patients recruited in the same clinical trial may have vastly different underlying biology, obscuring trial outcomes and making it difficult to determine the benefit of MSCs in subgroups of patients. An accumulating body of evidence indicates the importance of considering not only the cell product but also patient-specific biomarkers and/or immune characteristics in determining MSC responsiveness. A mode of action where intravascular MSC destruction is followed by monocyte-efferocytosis-mediated skewing of the immune repertoire in a permissive inflammatory environment would both explain why cell engraftment is irrelevant for MSC efficacy and stress the importance of biologic differences between responding and nonresponding patients. We recommend a combined analysis of clinical outcomes and both biomarkers of disease activity and MSC potency assays to identify patients with GvHD who are likely to benefit from MSC therapy.
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Affiliation(s)
- Nadir Kadri
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sylvie Amu
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ellen Iacobaeus
- Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
| | - Erik Boberg
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
| | - Katarina Le Blanc
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
- Department of Cell Therapies and Allogeneic Stem Cell Transplantation Karolinska University Hospital, Stockholm, Sweden.
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4
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Giacomini C, Granéli C, Hicks R, Dazzi F. The critical role of apoptosis in mesenchymal stromal cell therapeutics and implications in homeostasis and normal tissue repair. Cell Mol Immunol 2023; 20:570-582. [PMID: 37185486 DOI: 10.1038/s41423-023-01018-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 03/30/2023] [Indexed: 05/17/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have been extensively tested for the treatment of numerous clinical conditions and have demonstrated good safety but mixed efficacy. Although this outcome can be attributed in part to the heterogeneity of cell preparations, the lack of mechanistic understanding and tools to establish cell pharmacokinetics and pharmacodynamics, as well as the poorly defined criteria for patient stratification, have hampered the design of informative clinical trials. We and others have demonstrated that MSCs can rapidly undergo apoptosis after their infusion. Apoptotic MSCs are phagocytosed by monocytes/macrophages that are then reprogrammed to become anti-inflammatory cells. MSC apoptosis occurs when the cells are injected into patients who harbor activated cytotoxic T or NK cells. Therefore, the activation state of cytotoxic T or NK cells can be used as a biomarker to predict clinical responses to MSC treatment. Building on a large body of preexisting data, an alternative view on the mechanism of MSCs is that an inflammation-dependent MSC secretome is largely responsible for their immunomodulatory activity. We will discuss how these different mechanisms can coexist and are instructed by two different types of MSC "licensing": one that is cell-contact dependent and the second that is mediated by inflammatory cytokines. The varied and complex mechanisms by which MSCs can orchestrate inflammatory responses and how this function is specifically driven by inflammation support a physiological role for tissue stroma in tissue homeostasis, and it acts as a sensor of damage and initiator of tissue repair by reprogramming the inflammatory environment.
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Affiliation(s)
- Chiara Giacomini
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK.
| | - Cecilia Granéli
- BioPharmaceuticals R&D Cell Therapy Department, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Ryan Hicks
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
- BioPharmaceuticals R&D Cell Therapy Department, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Francesco Dazzi
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK.
- BioPharmaceuticals R&D Cell Therapy Department, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
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T Cell and Cytokine Dynamics in the Blood of Patients after Hematopoietic Stem Cell Transplantation and Multipotent Mesenchymal Stromal Cell Administration. Transplant Cell Ther 2023; 29:109.e1-109.e10. [PMID: 36372356 DOI: 10.1016/j.jtct.2022.10.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 09/28/2022] [Accepted: 10/31/2022] [Indexed: 11/13/2022]
Abstract
Multipotent mesenchymal stromal cells (MSCs) are currently under intensive investigation for the treatment and prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), owing to their substantial immunomodulatory properties. The responses of recipients to MSC infusion following allo-HSCT are not yet well understood. T cells are central to the adaptive immune system, protecting the organism from infection and malignant cells. Memory T cells with different phenotypes, gene expression profiles, and functional properties are critical for immune processes regulation. The aim of this study was to study the dynamics of memory T cell subpopulations and cytokines in the blood of allo-HSCT recipients after MSC administration. In clinical trial NCT01941394, patients after allo-HSCT were randomized into 2 groups, one receiving standard GVHD prophylaxis and the other also receiving MSC infusion on the day of leukocyte recovery to 1000 cells/μL (engraftment, day E0). Blood samples of patients from both groups were analyzed on days E0, E+3, and E+30. T cell subpopulations were studied by flow cytometry, and cytokine concentrations were evaluated by the Bio-Plex Pro Human Cytokine Panel. Administration of MSCs to patients on day E0 did not affect the overall dynamics of restoration of absolute numbers and proportions of T and B lymphocytes after 3 and 30 days. At 3 days after MSC injection, only the numbers of CD8+ effector cells (CD8+TE, CD8+TM, and CD8+EM) were found to increase significantly. A significant increase in the number of CD4+ cells after 30 days compared to day E0 was observed only in patients who received MSCs, indicating faster recovery of the CD4+ cell population following MSC injection. An increase in CD8+ cell number by day E+30 was significant regardless of MSC administration. To characterize the immune status of patients following allo-HSCT in more detail, changes in the cytokine concentration in the peripheral blood of patients on days E0, E+3, and E+30 after MSC administration were investigated. On day E+30, significant increases in the numbers of CD4+CM and activated CD4+CD25+ cells were observed. The concentrations of proinflammatory and anti-inflammatory cytokines IL-6, IL-8, IL-17, TNF-α, and IFN-γ were increased significantly in patients injected with MSCs. Analysis of growth factor levels showed that in the group of patients who received MSCs, the concentrations of G-CSF, GM-CSF, PDGFbb, FGFb, and IL-5 increased by day E+30. Among the cytokines involved in regulation of the immune response, concentrations of IL-9, eotaxin, IP-10, MCP-1, and MIP-1a were increased after 30 days irrespective of MSC administration. The administration of MSCs exerts a positive effect on the restoration of T cell subpopulations and immune system recovery in patients after allo-HSCT.
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6
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Tawfeek GAE, Eseily HA. A novel function of collagen/PCL nanofiber interaction with MSCs in osteoarthritis is potentiation its immunomodulatory effect through increased ICAM expression. Transpl Immunol 2022; 73:101625. [DOI: 10.1016/j.trim.2022.101625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 05/06/2022] [Accepted: 05/08/2022] [Indexed: 11/25/2022]
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7
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Li Y, Hao J, Hu Z, Yang YG, Zhou Q, Sun L, Wu J. Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: a systematic review. Stem Cell Res Ther 2022; 13:93. [PMID: 35246235 PMCID: PMC8895864 DOI: 10.1186/s13287-022-02751-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/31/2022] [Indexed: 12/11/2022] Open
Abstract
Background Graft-versus-host disease (GVHD) is a common fatal complication of hematopoietic stem cell transplantation (HSCT), where steroids are used as a treatment option. However, there are currently no second-line treatments for patients that develop steroid-resistance (SR). Mesenchymal stem cells (MSCs) have immunomodulatory functions and can exert immunosuppressive effects on the inflammatory microenvironment. A large number of in vitro experiments have confirmed that MSCs can significantly inhibit the proliferation or activation of innate and adaptive immune cells. In a mouse model of GVHD, MSCs improved weight loss and increased survival rate. Therefore, there is great promise for the clinical translation of MSCs for the prevention or treatment of GVHD, and several clinical trials have already been conducted to date. Main body In this study, we searched multiple databases and found 79 clinical trials involving the use of MSCs to prevent or treat GVHD and summarized the characteristics of these clinical trials, including study design, phase, status, and locations. We analyzed the results of these clinical trials, including the response and survival rates, to enable researchers to obtain a comprehensive understanding of the field’s progress, challenges, limitations, and future development trends. Additionally, factors that might result in inconsistencies in clinical trial results were discussed. Conclusion In this study, we attempted to analyze the clinical trials for MSCs in GVHD, identify the most suitable group of patients for MSC therapy, and provide a new perspective for the design of such trials in the future. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02751-0.
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Affiliation(s)
- Ying Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.,Department of Gastroenterology, The First Hospital, Jilin University, Changchun, 130021, China
| | - Jie Hao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zheng Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.,International Center of Future Science, Jilin University, Changchun, 130021, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Liguang Sun
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China. .,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.
| | - Jun Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China.
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8
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Schneider RS, Vela AC, Williams EK, Martin KE, Lam WA, García AJ. High-Throughput On-Chip Human Mesenchymal Stromal Cell Potency Prediction. Adv Healthc Mater 2022; 11:e2101995. [PMID: 34725948 PMCID: PMC8770576 DOI: 10.1002/adhm.202101995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 10/25/2021] [Indexed: 01/03/2023]
Abstract
Human mesenchymal stromal cells (hMSCs) are a promising source for regenerative cell therapy. However, hMSC clinical use has been stymied by product variability across hMSC donors and manufacturing practices resulting in inconsistent clinical outcomes. The inability to predict hMSC clinical efficacy, or potency, is a major limitation for market penetration. Standard metrics of hMSC potency employ hMSCs and third-party immune cell co-cultures, however, these assays face translational challenges due to third-party donor variability and lack of scalability. While surrogate markers of hMSC potency have been suggested, none have yet had translational success. To address this, a high-throughput, scalable, low-cost, on-chip microfluidic potency assay is presented with improved functional predictive power and recapitulation of in vivo secretory responses compared to traditional approaches. Comparison of hMSC secretory responses to functional hMSC-medicated immune cell suppression demonstrates shortcomings of current surrogate potency markers and identifies on-chip microfluidic potency markers with improved functional predictive power compared to traditional planar methods. Furthermore, hMSC secretory performance achieved in the on-chip microfluidic system has improved similarity compared to an in vivo model. The results underscore the shortcomings of current culture practices and present a novel system with improved functional predictive power and hMSC physiological responses.
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Affiliation(s)
- Rebecca S Schneider
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, 30318, USA
- Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA
| | - Alexandra C Vela
- Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA
- College of Sciences, Georgia Institute of Technology, Atlanta, GA, 30313, USA
| | - Evelyn Kendall Williams
- Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA, 30332, USA
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center & Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Karen E Martin
- Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30313, USA
| | - Wilbur A Lam
- Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA, 30332, USA
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center & Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Andrés J García
- Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30313, USA
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9
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Krampera M, Le Blanc K. Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy. Cell Stem Cell 2021; 28:1708-1725. [PMID: 34624232 DOI: 10.1016/j.stem.2021.09.006] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
An exceptional safety profile has been shown in a large number of cell therapy clinical trials that use mesenchymal stromal cells (MSCs). However, reliable potency assays are still lacking to predict MSC immunosuppressive efficacy in the clinical setting. Nevertheless, MSCs are approved in Japan and Europe for the treatment of graft-versus-host and Crohn's fistular diseases, but not in the United States for any clinical indication. We discuss potential mechanisms of action for the therapeutic effects of MSC transplantation, experimental models that dissect tissue modulating function of MSCs, and approaches for identifying MSC effects in vivo by integrating biomarkers of disease and MSC activity.
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Affiliation(s)
- Mauro Krampera
- Section of Hematology and Bone Marrow Transplant Unit, Department of Medicine, University of Verona, Verona, Italy.
| | - Katarina Le Blanc
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden; Center of Allogeneic Stem Cell Transplantation and Cellular Therapy (CAST), Karolinska University Hospital, Huddinge, Stockholm, Sweden.
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10
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Andres AM, Stringa P, Talayero P, Santamaria M, García-Arranz M, García Gómez-Heras S, Largo-Aramburu C, Aras-Lopez RM, Vallejo-Cremades MT, Guerra Pastrián L, Vega L, Encinas JL, Lopez-Santamaria M, Hernández-Oliveros F. Graft infusion of adipose-derived mesenchymal stromal cells to prevent rejection in experimental intestinal transplantation: A feasibility study. Clin Transplant 2021; 35:e14226. [PMID: 33465824 DOI: 10.1111/ctr.14226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/30/2020] [Accepted: 01/12/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Mesenchymal stromal cells (MSC) have been proposed as a promising complement to standard immunosuppression in solid organ transplantation because of their immunomodulatory properties. The present work addresses the role of adipose-derived MSC (Ad-MSC) in an experimental model of acute rejection in small bowel transplantation (SBT). MATERIAL/METHODS Heterotopic allogeneic SBT was performed. A single dose of 1.5x106 Ad-MSC was intra-arterially delivered just before graft reperfusion. Animals were divided into CONTROL (CTRL), CONTROL+Ad-MSC (CTRL_MSC), tacrolimus (TAC), and TAC+Ad-MSC (TAC_MSC) groups. Each Ad-MSC groups was subdivided in autologous and allogeneic third-party groups. RESULTS Rejection rate and severity were similar in MSC-treated and untreated animals. CTRL_MSC animals showed a decrease in macrophages, T-cell (CD4, CD8, and Foxp3 subsets) and B-cell counts in the graft compared with CTRL, this decrease was attenuated in TAC_MSC animals. Pro- and anti-inflammatory cytokines and some chemokines and growth factors increased in CTRL_MSC animals, especially in the allogeneic group, whereas milder changes were seen in the TAC groups. CONCLUSION Ad-MSC did not prevent rejection when administered just before reperfusion. However, they showed immunomodulatory effects that could be relevant for a longer-term outcome. Interference between tacrolimus and the MSC effects should be addressed in further studies.
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Affiliation(s)
- Ane M Andres
- Pediatric Surgery Department, La Paz University Hospital, Madrid, Spain.,Idipaz Institute, La Paz University Hospital, Madrid, Spain.,TransplantChild ERN, Idipaz Institute, La Paz University Hospital, Madrid, Spain
| | - Pablo Stringa
- Institute for Immunological and Physiopathological Studies (IIFP-CONICET-UNLP), National University of La Plata, Buenos Aires, Argentina
| | - Paloma Talayero
- Immunology Department, 12 de Octubre University Hospital, Madrid, Spain.,imas12 Research Institute, 12 de Octubre University Hospital, Madrid, Spain
| | - Monica Santamaria
- Experimental Transplant Department, Alfonso X University, Madrid, Spain
| | | | | | | | - Rosa M Aras-Lopez
- Research Institute, Idipaz Institute, La Paz University Hospital, Madrid, Spain
| | | | | | - Luz Vega
- Health Research Institute, Fundación Jimenez Diaz, Madrid, Spain
| | - Jose Luis Encinas
- Pediatric Surgery Department, La Paz University Hospital, Madrid, Spain
| | | | - Francisco Hernández-Oliveros
- TransplantChild ERN, Idipaz Institute, La Paz University Hospital, Madrid, Spain.,Health Research Institute, Fundación Jimenez Diaz, Madrid, Spain.,Pediatric Surgery Department EOC TransplantChild ERN, La Paz University Hospital, Madrid, Spain
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11
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Zorina T, Black L. Mesenchymal–Hematopoietic Stem Cell Axis: Applications for Induction of Hematopoietic Chimerism and Therapies for Malignancies. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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12
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Zorina TD. New Insights on the Role of the Mesenchymal-Hematopoietic Stem Cell Axis in Autologous and Allogeneic Hematopoiesis. Stem Cells Dev 2020; 30:2-16. [PMID: 33231142 DOI: 10.1089/scd.2020.0148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Cytoreductive protocols are integral both as conditioning regimens for bone marrow (BM) transplantation and as part of therapies for malignancies, but their associated comorbidities represent a long-standing clinical problem. In particular, they cause myeloablation that debilitates the physiological role of mesenchymal stem and precursor cells (MSPCs) in sustaining hematopoiesis. This review addresses the damaging impact of cytoreductive regimens on MSPCs. In addition, it discusses prospects for alleviating the resulting iatrogenic comorbidities. New insights into the structural and functional dynamics of hematopoietic stem cell (HSC) niches reveal the existence of "empty" niches and the ability of the donor-derived healthy HSCs to outcompete the defective HSCs in occupying these niches. These findings support the notion that conditioning regimens, conventionally used to ablate the recipient hematopoiesis to create space for engraftment of the donor-derived HSCs, may not be a necessity for allogeneic BM transplantation. In addition, the capacity of the MSPCs to cross-talk with HSCs, despite major histocompatibility complex disparity, and suppress graft versus host disease indicates the possibility for development of a conditioning-free, MSPCs-enhanced protocol for BM transplantation. The clinical advantage of supplementing cytoreductive protocols with MSPCs to improve autologous hematopoiesis reconstitution and alleviate cytopenia associated with chemo and radiation therapies for cancer is also discussed.
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Affiliation(s)
- Tatiana D Zorina
- Department of Medical Laboratory Science and Biotechnology, Jefferson College of Health Professions, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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13
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Cheung TS, Bertolino GM, Giacomini C, Bornhäuser M, Dazzi F, Galleu A. Mesenchymal Stromal Cells for Graft Versus Host Disease: Mechanism-Based Biomarkers. Front Immunol 2020; 11:1338. [PMID: 32670295 PMCID: PMC7330053 DOI: 10.3389/fimmu.2020.01338] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 05/26/2020] [Indexed: 12/13/2022] Open
Abstract
The immunosuppressive activity of mesenchymal stromal cells (MSCs) in graft versus host disease (GvHD) is well-documented, but their therapeutic benefit is rather unpredictable. Prospective randomized clinical trials remain the only means to address MSC clinical efficacy. However, the imperfect understanding of MSC biological mechanisms has undermined patients' stratification and the successful design of clinical studies. Furthermore, although MSC efficacy seems to be dependent on patient-associated factors, the role of patients' signature to predict and/or monitor clinical outcomes remains poorly elucidated. The analysis of GvHD patient serum has identified a set of molecules that are associated with high mortality. However, despite their importance in defining GvHD severity, their role in predicting or monitoring response to MSCs has not been confirmed. A new perspective on the use of MSCs for GvHD has been prompted by the recent findings that MSCs are actively induced to undergo apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. This discovery has not only reconciled the conundrum between MSC efficacy and their lack of engraftment, but also highlighted the determinant role of the patient in promoting and delivering MSC immunosuppression. In this review we will revisit the extensive use of MSCs for the treatment of GvHD and will elaborate on the need that future clinical trials must depend on mechanistic approaches that facilitate the development of robust and consistent assays to stratify patients and monitor clinical outcomes.
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Affiliation(s)
- Tik Shing Cheung
- School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom
| | - Giuliana Minani Bertolino
- School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom
| | - Chiara Giacomini
- School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom
| | | | - Francesco Dazzi
- School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom
| | - Antonio Galleu
- School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom
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Kurtzberg J, Prockop S, Chaudhury S, Horn B, Nemecek E, Prasad V, Satwani P, Teira P, Hayes J, Burke E. Study 275: Updated Expanded Access Program for Remestemcel-L in Steroid-Refractory Acute Graft-versus-Host Disease in Children. Biol Blood Marrow Transplant 2020; 26:855-864. [PMID: 32044400 PMCID: PMC8292970 DOI: 10.1016/j.bbmt.2020.01.026] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/30/2020] [Accepted: 01/31/2020] [Indexed: 01/08/2023]
Abstract
Clinical outcomes in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD) are generally poor, with a high mortality rate and limited therapeutic options. Here we report our updated investigational experience with mesenchymal stromal cell (MSC) therapy with remestemcel-L in a multicenter expanded access protocol (ClinicalTrials.gov identifier NCT00759018) in 241 children with aGVHD who failed to respond to steroids with or without other secondary and tertiary immunosuppressive therapies. A total of 241 children with grade B-D SR-aGVHD were enrolled at 50 sites in 8 countries and received 8 biweekly i.v. infusions of human MSCs, 2 × 106 per kg for 4 weeks, with an option for an additional 4 weekly infusions after day +28 for subjects who achieved either a partial response (PR) or mixed response. The mean age of the subjects was 9.6 years; 39% were female, and 60% were white. Most of the subjects had grade C (30%) or grade D (50%) disease, and in most cases, the subjects had failed to respond to other immunosuppressive agents after failing steroids. The primary endpoint was overall response (OR; the sum of complete response [CR] and PR) at day +28. Across all subjects, a 28-day OR was observed in 157 patients (65.1%), with 34 (14.1%) achieving CR and 123 (51.3%) achieving PR. Stratified by aGVHD grade at baseline, the OR rate at day +28 was 72.9% for patients with aGVHD grade B, 67.1% for those with aGVHD grade C, and 60.8% for those with aGVHD grade D. Survival through day +100, a secondary endpoint of the study, was 66.9% (n = 160 of 239). Importantly, survival through day +100 was significantly greater in subjects who achieved a day +28 OR compared with nonresponders (82.1% versus 38.6%; P < .001, log-rank test). Remestemcel-L safety was generally well tolerated, with no infusional toxicity and no identified safety concerns. In summary, this update to the remestemcel-L expanded access program confirms the reported clinical and survival benefits of remestemcel-L therapy in children with aGVHD who have exhausted all conventional therapeutic options.
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Affiliation(s)
| | - Susan Prockop
- MSK Kids Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sonali Chaudhury
- Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | | | - Eneida Nemecek
- Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon
| | - Vinod Prasad
- Duke University Medical Center, Durham, North Carolina
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Zhang J, Liu Y, Yin W, Hu X. Adipose-derived stromal cells in regulation of hematopoiesis. Cell Mol Biol Lett 2020; 25:16. [PMID: 32161623 PMCID: PMC7059705 DOI: 10.1186/s11658-020-00209-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 02/25/2020] [Indexed: 12/21/2022] Open
Abstract
Over the past decade, mesenchymal stromal cells (MSCs) found in the bone marrow microenvironment have been considered to be important candidates in cellular therapy. However, the application of MSCs in clinical settings is limited by the difficulty and low efficiency associated with the separation of MSCs from the bone marrow. Therefore, distinct sources of MSCs have been extensively explored. Adipose-derived stromal cells (ASCs), a cell line similar to MSCs, have been identified as a promising source. ASCs have become increasingly popular in many fields, as they can be conveniently extracted from fat tissue. This review focuses on the properties of ASCs in hematopoietic regulation and the underlying mechanisms, as well as the current applications and future perspectives in ASC-based therapy.
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Affiliation(s)
- Jing Zhang
- 1Department of Transfusion Medicine, Xijing Hospital, Xi'an, 710032 China
| | - Yunsheng Liu
- 2Department of Rocket Force Medicine, Third Military Medical University, Chongqing, 400038 China
| | - Wen Yin
- 1Department of Transfusion Medicine, Xijing Hospital, Xi'an, 710032 China
| | - Xingbin Hu
- 1Department of Transfusion Medicine, Xijing Hospital, Xi'an, 710032 China
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16
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A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 2020; 26:845-854. [PMID: 32018062 PMCID: PMC8322819 DOI: 10.1016/j.bbmt.2020.01.018] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/17/2020] [Accepted: 01/26/2020] [Indexed: 12/17/2022]
Abstract
Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well tolerated, and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single-arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies for aGVHD treated with MSC product (remestemcel-L) dosed at 2 × 106 cells/kg twice weekly for 4 weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared with the prespecified control OR value of 45% (70.4% versus 45%, P = .0003). The statistically significant OR (70.4%) was sustained through day 100, including an increase in complete response from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days, and survival was significantly greater in day 28 responders compared with nonresponders through day 100 (86.8% versus 47.1% for responders and nonresponders, respectively, P = .0001) and through day 180 (78.9% versus 43.8%, P = .003). Remestemcel-L was well tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability, and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.
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Black L, Zorina T. Cell-based immunomodulatory therapy approaches for type 1 diabetes mellitus. Drug Discov Today 2020; 25:380-391. [DOI: 10.1016/j.drudis.2019.11.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/11/2019] [Accepted: 11/30/2019] [Indexed: 12/14/2022]
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Hinden L, Avner M, Stepensky P, Or R, Almogi-Hazan O. Lymphocyte counts may predict a good response to mesenchymal stromal cells therapy in graft versus host disease patients. PLoS One 2019; 14:e0217572. [PMID: 31188842 PMCID: PMC6561566 DOI: 10.1371/journal.pone.0217572] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 05/14/2019] [Indexed: 01/08/2023] Open
Abstract
Steroid-resistant GvHD is one of the most significant causes of mortality following allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Treatment with mesenchymal stromal cells (MSC) seems to be a promising solution, however the results from clinical studies are still equivocal. Better selection of candidate patients and improving monitoring of patients following MSC administration can increase treatment effectiveness. In order to determine which characteristics can be used to predict a good response and better monitoring of patients, blood samples were taken prior to therapy, one week and one month after therapy, from 26 allogeneic HSCT patients whom contracted GvHD and were treated with MSCs. Samples were examined for differential blood counts, bilirubin levels and cell surface markers. Serum cytokine levels were also measured. We found that the level of lymphocytes, in particular T and NK cells, may predict a good response to therapy. A better response was observed among patients who expressed low levels of IL-6 and IL-22, Th17 related cytokines, prior to therapy. Patients with high levels of bilirubin prior to therapy showed a poorer response. The results of this study may facilitate early prediction of success or failure of the treatment, and subsequently, will improve selection of patients for MSC therapy.
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Affiliation(s)
- Liad Hinden
- Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Mordechai Avner
- Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Polina Stepensky
- Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Reuven Or
- Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Osnat Almogi-Hazan
- Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Mazini L, Rochette L, Amine M, Malka G. Regenerative Capacity of Adipose Derived Stem Cells (ADSCs), Comparison with Mesenchymal Stem Cells (MSCs). Int J Mol Sci 2019; 20:ijms20102523. [PMID: 31121953 PMCID: PMC6566837 DOI: 10.3390/ijms20102523] [Citation(s) in RCA: 262] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/03/2019] [Accepted: 05/06/2019] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue is now on the top one of stem cell sources regarding its accessibility, abundance, and less painful collection procedure when compared to other sources. The adipose derived stem cells (ADSCs) that it contains can be maintained and expanded in culture for long periods of time without losing their differentiation capacity, leading to large cell quantities being increasingly used in cell therapy purposes. Many reports showed that ADSCs-based cell therapy products demonstrated optimal efficacy and efficiency in some clinical indications for both autologous and allogeneic purposes, hence becoming considered as potential tools for replacing, repairing, and regenerating dead or damaged cells. In this review, we analyzed the therapeutic advancement of ADSCs in comparison to bone marrow (BM) and umbilical cord (UC)-mesenchymal stem cells (MSCs) and designed the specific requirements to their best clinical practices and safety. Our analysis was focused on the ADSCs, rather than the whole stromal vascular fraction (SVF) cell populations, to facilitate characterization that is related to their source of origins. Clinical outcomes improvement suggested that these cells hold great promise in stem cell-based therapies in neurodegenerative, cardiovascular, and auto-immunes diseases.
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Affiliation(s)
- Loubna Mazini
- Laboratoire Cellules Souches et Ingénierie Tissulaire, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
| | - Luc Rochette
- Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne Franche Comté, Faculté des Sciences de Santé, 7 Bd Jeanne d'Arc, 21000 Dijon, France.
| | - Mohamed Amine
- Laboratoire d'Epidémiologie et de Biostatique, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
- Département de Santé Publique et de Médecine Communautaire, Faculté de Médecine et de Pharmacie, Université Cadi Ayyad, Marrakech 40000, Morocco.
| | - Gabriel Malka
- Laboratoire Cellules Souches et Ingénierie Tissulaire, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
- Laboratoire d'Epidémiologie et de Biostatique, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
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20
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Mazini L, Rochette L, Amine M, Malka G. Regenerative Capacity of Adipose Derived Stem Cells (ADSCs), Comparison with Mesenchymal Stem Cells (MSCs). Int J Mol Sci 2019. [PMID: 31121953 DOI: 10.3390/ijms20102523.pmid:31121953;pmcid:pmc6566837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023] Open
Abstract
Adipose tissue is now on the top one of stem cell sources regarding its accessibility, abundance, and less painful collection procedure when compared to other sources. The adipose derived stem cells (ADSCs) that it contains can be maintained and expanded in culture for long periods of time without losing their differentiation capacity, leading to large cell quantities being increasingly used in cell therapy purposes. Many reports showed that ADSCs-based cell therapy products demonstrated optimal efficacy and efficiency in some clinical indications for both autologous and allogeneic purposes, hence becoming considered as potential tools for replacing, repairing, and regenerating dead or damaged cells. In this review, we analyzed the therapeutic advancement of ADSCs in comparison to bone marrow (BM) and umbilical cord (UC)-mesenchymal stem cells (MSCs) and designed the specific requirements to their best clinical practices and safety. Our analysis was focused on the ADSCs, rather than the whole stromal vascular fraction (SVF) cell populations, to facilitate characterization that is related to their source of origins. Clinical outcomes improvement suggested that these cells hold great promise in stem cell-based therapies in neurodegenerative, cardiovascular, and auto-immunes diseases.
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Affiliation(s)
- Loubna Mazini
- Laboratoire Cellules Souches et Ingénierie Tissulaire, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
| | - Luc Rochette
- Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne Franche Comté, Faculté des Sciences de Santé, 7 Bd Jeanne d'Arc, 21000 Dijon, France.
| | - Mohamed Amine
- Laboratoire d'Epidémiologie et de Biostatique, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
- Département de Santé Publique et de Médecine Communautaire, Faculté de Médecine et de Pharmacie, Université Cadi Ayyad, Marrakech 40000, Morocco.
| | - Gabriel Malka
- Laboratoire Cellules Souches et Ingénierie Tissulaire, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
- Laboratoire d'Epidémiologie et de Biostatique, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
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21
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Pers YM, Quentin J, Feirreira R, Espinoza F, Abdellaoui N, Erkilic N, Cren M, Dufourcq-Lopez E, Pullig O, Nöth U, Jorgensen C, Louis-Plence P. Injection of Adipose-Derived Stromal Cells in the Knee of Patients with Severe Osteoarthritis has a Systemic Effect and Promotes an Anti-Inflammatory Phenotype of Circulating Immune Cells. Theranostics 2018; 8:5519-5528. [PMID: 30555561 PMCID: PMC6276295 DOI: 10.7150/thno.27674] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 10/01/2018] [Indexed: 12/14/2022] Open
Abstract
Rationale: Recent studies confirmed that osteoarthritis (OA) is associated with systemic inflammation. Adipose-derived stromal cells (ASCs) could become the most promising cell-based therapy in OA, based not only on their differentiation capacities and trophic and paracrine effects on the existing cartilage, but also on their immunomodulatory properties. Here, we wanted to determine the biological effect of autologous ASC intra-articular (IA) injection. Method: To this aim, we monitored the profile of immune cells in fresh peripheral blood after IA injection of autologous ASCs in the knee of 18 patients with severe OA (ADIPOA phase I study). Specifically, we used 8-color flow cytometry antibody panels to characterize the frequencies of innate and adaptive immune cell subsets (monocytes, dendritic cells, regulatory T cells and B cells) in blood samples at baseline (before injection) and one week, one month and three months after ASC injection. Results: We found that the percentage of CD4+CD25highCD127lowFOXP3+ regulatory T cells was significantly increased at 1 month after ASC injection, and this effect persisted for at least 3 months. Moreover, CD24highCD38high transitional B cells also were increased, whereas the percentage of classical CD14+ monocytes was decreased, at 3 months after ASC injection. These results suggest a global switch toward regulatory immune cells following IA injection of ASCs, underscoring the safety of ASC-based therapy. We did not find any correlation between the scores for the Visual Analogic Scale for pain, the Western Ontario and McMaster Universities Osteoarthritis Index (pain subscale and total score) at baseline and the immune cell profile changes, but this could be due to the small number of analyzed patients. Conclusion: ASCs may drive an immediate local response by releasing paracrine factors and cytokines, and our results suggest that ASCs could also initiate a cascade resulting in a long-lasting systemic immune modulation.
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22
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Seng A, Dunavin N. Mesenchymal stromal cell infusions for acute graft-versus-host disease: Rationale, data, and unanswered questions. ACTA ACUST UNITED AC 2018. [DOI: 10.1002/acg2.14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Amara Seng
- Department of Microbiology; Molecular Genetics and Immunology; University of Kansas Medical Center; Kansas City Kansas
| | - Neil Dunavin
- Division of Hematological Malignancies and Cellular Therapeutics; Department of Internal Medicine; University of Kansas Medical Center; Kansas City Kansas
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23
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Yang Y, He X, Zhao R, Guo W, Zhu M, Xing W, Jiang D, Liu C, Xu X. Serum IFN-γ levels predict the therapeutic effect of mesenchymal stem cell transplantation in active rheumatoid arthritis. J Transl Med 2018; 16:165. [PMID: 29903026 PMCID: PMC6003078 DOI: 10.1186/s12967-018-1541-4] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 06/06/2018] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND To explore the mechanism of the different clinical efficacies of mesenchymal stem cell transplantation (MSCT) and identify a possible serum biomarker for predicting the therapeutic effect of MSCT in rheumatoid arthritis (RA) patients. METHODS A total of 105 patients with persistently active RA and poor responses to traditional medication were randomly divided into MSCT and control groups. Outcomes were evaluated according to the 28-joint Disease Activity Score and Health Assessment Questionnaire, serological indicators, regulatory T cell (Treg) to T helper 17 (Th17) cell ratio, and inflammatory cytokine levels. Twelve weeks after MSCT, the outcomes of the MSCT group were evaluated according to the European League against Rheumatism response criteria. Patients with a good or moderate response were added to the response group, and those with no response were added to the no-response group. RESULTS No serious adverse events were reported for either MSCT subgroup (28 in the response group and 24 in the no-response group). The therapeutic effects lasted for 48 weeks without continuous administration. Notably, a transient increase in serum IFN-γ (>2 pg/ml) levels was observed in the response group, but not in the no-response group. Furthermore, an increase in IL-10 levels and the Treg/Th17 ratio and a reduction in IL-6 levels appeared 2-3 weeks after the transient IFN-γ increase. CONCLUSIONS Allogeneic MSCT is safe and feasible, and we propose high serum IFN-γ levels as a potent biomarker for predicting MSCT response. Trial registration chictr.org, ChiCTR-ONC-16008770. Registered 3 July 2016, http://www.chictr.org.cn/showproj.aspx?proj=14820.
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Affiliation(s)
- Yi Yang
- First Department, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 400042 People’s Republic of China
- Department of Rheumatology and Clinical Immunology, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 400042 People’s Republic of China
| | - Xiao He
- First Department, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 400042 People’s Republic of China
| | - Rongseng Zhao
- First Department, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 400042 People’s Republic of China
| | - Wei Guo
- First Department, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 400042 People’s Republic of China
| | - Ming Zhu
- First Department, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 400042 People’s Republic of China
| | - Wei Xing
- First Department, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 400042 People’s Republic of China
| | - Dongpo Jiang
- Department of Critical Care Medicine, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 400042 People’s Republic of China
| | - Chongyang Liu
- Department of Rheumatology and Clinical Immunology, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 400042 People’s Republic of China
| | - Xiang Xu
- First Department, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 400042 People’s Republic of China
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Han N, Xiao Y. [Research status and application prospect of mesenchymal stem cells in hematological diseases]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2018; 39:346-349. [PMID: 29779338 PMCID: PMC7342131 DOI: 10.3760/cma.j.issn.0253-2727.2018.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Indexed: 11/07/2022]
Affiliation(s)
| | - Y Xiao
- Department of Hematology, Guangzhou General Hospital of Guangzhou Military Command of PLA, Southern Medical University, Guangdong 510010, China
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25
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Keto J, Kaartinen T, Salmenniemi U, Castrén J, Partanen J, Hänninen A, Korhonen M, Lähteenmäki K, Itälä-Remes M, Nystedt J. Immunomonitoring of MSC-Treated GvHD Patients Reveals Only Moderate Potential for Response Prediction but Indicates Treatment Safety. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2018. [PMID: 29516024 PMCID: PMC5834657 DOI: 10.1016/j.omtm.2018.02.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Mesenchymal stromal cells (MSCs) are used as salvage therapy to treat steroid-refractory acute graft-versus-host disease (aGvHD). We studied the immunological response to MSC treatment in 16 aGvHD patients by assessing lymphocyte profiles and three proposed aGvHD serum markers during the MSC treatment. Surprisingly, there were no obvious differences in the lymphocyte profiles between the responders and non-responders. The numbers of T, B, and NK cells were below the normal reference interval in all patients. CD4+ T helper (Th) cell levels remained particularly low throughout the follow-up period. The relative proportion of Th1 cells decreased, while regulatory T cells remained unaltered, and only very few Th2 and Th17 cells could be detected. Serum concentrations of regenerating islet-derived protein 3-alpha, cytokeratin-18 fragments (CK18F), and elafin were significantly elevated in patient samples compared with healthy controls, but only CK18F showed any potential in the prediction of patients’ response to MSCs. No obvious markers for MSC therapy response were revealed in this study, but the results suggest that allogeneic MSCs do not provoke overt T cell-mediated immune responses at least in immunosuppressed aGvHD patients. The results advocate for the safety of MSC therapy and bring new insights in MSC immunomodulation mechanisms.
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Affiliation(s)
- Joni Keto
- Finnish Red Cross Blood Service, Kivihaantie 7, FI-00310 Helsinki, Finland
| | - Tanja Kaartinen
- Finnish Red Cross Blood Service, Kivihaantie 7, FI-00310 Helsinki, Finland
| | - Urpu Salmenniemi
- Division of Medicine, Department of Hematology and Stem Cell Transplantation Unit, Turku University Hospital, Hämeentie 11, FI-20521 Turku, Finland
| | - Johanna Castrén
- Finnish Red Cross Blood Service, Kivihaantie 7, FI-00310 Helsinki, Finland
| | - Jukka Partanen
- Finnish Red Cross Blood Service, Kivihaantie 7, FI-00310 Helsinki, Finland
| | - Arno Hänninen
- Department of Medical Microbiology and Immunology, University of Turku, Kiinamyllynkatu 13, FI-20520 Turku, Finland
| | - Matti Korhonen
- Finnish Red Cross Blood Service, Kivihaantie 7, FI-00310 Helsinki, Finland
| | | | - Maija Itälä-Remes
- Division of Medicine, Department of Hematology and Stem Cell Transplantation Unit, Turku University Hospital, Hämeentie 11, FI-20521 Turku, Finland
| | - Johanna Nystedt
- Finnish Red Cross Blood Service, Kivihaantie 7, FI-00310 Helsinki, Finland
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26
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Vertès AA. Methods and practices to diversify cell-based products. Regen Med 2017; 12:997-1013. [PMID: 29243940 DOI: 10.2217/rme-2017-0093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Medicinal signaling cell (MSC)-based products represent emerging treatments in various therapeutic areas including cardiometabolic, inflammation, autoimmunity, orthopedics, wound healing and oncology. Exploring innovation beyond minimally manipulated plastic-adherent ex vivo expanded allogeneic MSCs enables product delineation. Product delineation is on the critical path to maximize clinical benefits and market access. An innovation framework is presented here along various innovation dimensions comprising composition-of-matter by means of positive cell surface markers, formulation varying for example the cell dose or the preservation mode and medium, manufacturing to adapt the secretome of MSCs to the condition of interest, the mode of delivery and corresponding delivery devices, as well as molecular engineering and biomarkers. The rationale of the innovation space thus described applies generally to all cell-based therapies.
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Affiliation(s)
- Alain A Vertès
- London Business School, UK & NxR Biotechnologies GmbH, Basel, Switzerland
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27
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Bernardo ME, Locatelli F. Mesenchymal Stromal Cells in Hematopoietic Stem Cell Transplantation. Methods Mol Biol 2017; 1416:3-20. [PMID: 27236663 DOI: 10.1007/978-1-4939-3584-0_1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Mesenchymal stromal cells (MSCs) comprise a heterogeneous population of multipotent cells that can be isolated from various human tissues and cultured ex vivo for clinical use. Thanks to their secretion of growth factors, immunomodulatory properties and cell-to-cell interactions, MSCs play a key role in the regulation of hematopoiesis and in the modulation of immune responses against allo- and autoantigens. In light of these properties, MSCs have been employed in clinical trials in the context of hematopoietic stem cell transplantation (HSCT) to prevent/treat graft rejection and to treat steroid-resistant acute graft-versus-host disease (GvHD). The available clinical evidence derived from these studies indicates that MSC administration is safe; moreover, promising preliminary results in terms of efficacy have been reported in some clinical trials. This chapter focuses on recent advances in MSC therapy by reporting on the most important relevant studies in the field of HSCT.
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Affiliation(s)
- Maria Ester Bernardo
- Dipartimento di Emato-Oncologia e Medicina Trasfusionale, IRCCS Ospedale Pediatrico Bambino Gesù, P.le S. Onofrio, 00165, Rome, Italy.
| | - Franco Locatelli
- Dipartimento di Emato-Oncologia e Medicina Trasfusionale, IRCCS Ospedale Pediatrico Bambino Gesù, P.le S. Onofrio, 00165, Rome, Italy.,Dipartimento di Scienze Pediatriche, Università degli Studi di Pavia, Pavia, Italy
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Tissue regeneration: The crosstalk between mesenchymal stem cells and immune response. Cell Immunol 2017; 326:86-93. [PMID: 29221689 DOI: 10.1016/j.cellimm.2017.11.010] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 11/18/2017] [Accepted: 11/18/2017] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) exist in almost all tissues with the capability to differentiate into several different cell types and hold great promise in tissue repairs in a cell replacement manner. The study of the bidirectional regulation between MSCs and immune response has ushered an age of rethinking of tissue regeneration in the process of stem cell-based tissue repairs. By sensing damaged signals, both endogenous and exogenous MSCs migrate to the damaged site where they involve in the reconstitution of the immune microenvironment and empower tissue stem/progenitor cells and other resident cells, whereby facilitate tissue repairs. This MSC-based therapeutic manner is conferred as cell empowerment. In this process, MSCs have been found to exert extensive immunosuppression on both innate and adaptive immune response, while such regulation needs to be licensed by inflammation. More importantly, the immunoregulation of MSCs is highly plastic, especially in the context of pathological microenvironment. Understanding the immunoregulatory properties of MSCs is necessary for appropriate application of MSCs. Here we review the current studies on the crosstalk of MSCs and immune response in disease pathogenesis and therapy.
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LL-37 boosts immunosuppressive function of placenta-derived mesenchymal stromal cells. Stem Cell Res Ther 2016; 7:189. [PMID: 28038684 PMCID: PMC5203704 DOI: 10.1186/s13287-016-0448-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 11/16/2016] [Accepted: 11/23/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Although promising for graft-versus-host disease (GvHD) treatment, MSC therapy still faces important challenges. For instance, increasing MSC migratory capacity as well as potentializing immune response suppression are of interest. For GvHD management, preventing opportunistic infections is also a valuable strategy, since immunocompromised patients are easy targets for infections. LL-37 is a host defense peptide (HDP) that has been deeply investigated due to its immunomodulatory function. In this scenario, the combination of MSC and LL-37 may result in a robust combination to be clinically used. METHODS In the present study, the effects of LL-37 upon the proliferation and migratory capacity of human placenta-derived MSCs (pMSCs) were assessed by MTT and wound scratch assays. The influence of LL-37 over the immunosuppressive function of pMSCs was then investigated using CFSE cell division kit. Flow cytometry and real-time PCR were used to investigate the molecular mechanisms involved in the effects observed. RESULTS LL-37 had no detrimental effects over MSC proliferation and viability, as assessed by MTT assay. Moreover, the peptide promoted increased migratory behavior of pMSCs and enhanced their immunomodulatory function over activated human PBMCs. Strikingly, our data shows that LL-37 treatment leads to increased TLR3 levels, as shown by flow cytometry, and to an increased expression of factors classically related to immunosuppression, namely IDO, IL-10, TGF-β, IL-6, and IL-1β. CONCLUSIONS Taken together, our observations may serve as groundwork for the development of new therapeutic strategies based on the combined use of LL-37 and MSCs, which may provide patients not only with an enhanced immunosuppression regime, but also with an agent to prevent opportunistic infections.
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Vinci P, Bastone A, Schiarea S, Cappuzzello C, Del Prete A, Dander E, Biondi A, D'Amico G. Mesenchymal stromal cell-secreted chemerin is a novel immunomodulatory molecule driving the migration of ChemR23-expressing cells. Cytotherapy 2016; 19:200-210. [PMID: 27939374 DOI: 10.1016/j.jcyt.2016.11.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 10/25/2016] [Accepted: 11/05/2016] [Indexed: 12/29/2022]
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) are multipotent cells characterized by broad immunomodulatory properties exploited for the treatment of inflammatory disorders. However, the efficacy of MSC-based therapy is highly variable and tightly linked to MSC culture conditions and treatment schedule. Thus, the identification of novel key molecules regulating MSC immunomodulatory activities in vivo might constitute a crucial step toward the optimization of currently available clinical protocols. In this regard, herein, we sought to determine whether the newly identified chemotactic protein, chemerin, plays a role in MSC-mediated regulation of inflammation. METHODS Chemerin production by human MSCs was investigated under different culture conditions using enzyme-linked immunosorbent assay (ELISA). After purification, MSC-secreted chemerin was identified using mass spectrometry analysis and the biological activity of secreted isoforms was evaluated using migration assay. RESULTS Bone marrow-derived MSCs secrete chemerin and express its receptors ChemR23 and CCRL2. Chemerin production is dependent on culture conditions and increases upon stimulation with inflammatory cytokines. In particular, platelet lysate (PL)-MSCs produce higher levels of chemerin compared with fetal bovine serum (FBS)-MSCs. Furthermore, chemerin is secreted by MSCs as an inactive precursor, which can be converted into its active form by exogenous chemerin-activating serine and cysteine proteases. DISCUSSION Our data indicate that, in response to various inflammatory stimuli, MSCs secrete high amounts of inactive chemerin, which can then be activated by inflammation-induced tissue proteases. In light of these initial findings, we propose that further analysis of chemerin functions in vivo might constitute a crucial step toward optimizing MSC-based therapy for inflammatory diseases.
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Affiliation(s)
- Paola Vinci
- Centro di Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy
| | - Antonio Bastone
- Istituto di ricovero e cura a carattere scientifico-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Silvia Schiarea
- Istituto di ricovero e cura a carattere scientifico-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
| | - Claudia Cappuzzello
- Centro di Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy
| | - Annalisa Del Prete
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Humanitas Clinical and Research Center, Rozzano, Italy
| | - Erica Dander
- Centro di Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy
| | - Andrea Biondi
- Centro di Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy; Clinica Pediatrica, Università di Milano-Bicocca, Fondazione Monza e Brianza per il Bambino e la sua Mamma/Ospedale S. Gerardo, Monza, Italy
| | - Giovanna D'Amico
- Centro di Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
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Locatelli F, Algeri M, Trevisan V, Bertaina A. Remestemcel-L for the treatment of graft versus host disease. Expert Rev Clin Immunol 2016; 13:43-56. [PMID: 27399600 DOI: 10.1080/1744666x.2016.1208086] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Remestemcel-L, a third-party, off-the-shelf preparation of bone-marrow derived mesenchymal stromal cells (MSCs), has been developed for experimental use in acute graft-versus-host disease (aGvHD) and other immune-mediated conditions. Several preclinical and clinical studies have indeed suggested the potential of human mesenchymal stromal cells (MSCs) as an effective treatment for steroid-refractory aGvHD. However, an unambiguous demonstration of efficacy is still lacking. Areas covered: This review critically examines the biologic rationale supporting MSCs use in aGvHD and analyzes the results of published clinical trials in this setting, with a particular focus on the potential benefits and drawbacks of Remestemcel-L. For this purpose, a systematic literature search was performed in PubMed using the following keywords: 'mesenchymal stromal cells', 'mesenchymal progenitor cells', 'multipotent stromal cells', 'mesenchymal cells', 'MSC', 'Remestemcel-L', 'Prochymal', and 'graft-versus-host disease' or 'GvHD'. Expert commentary: Remestemcel-L represents a promising alternative to second-line immunosuppressive agents for the treatment of steroid-refractory aGvHD. Despite the safety and the favorable risk/benefit profile of this cell product, which has been demonstrated in several phase I-II studies, large and prospective randomized trials are required to confirm its efficacy in aGvHD and to define the optimal schedule of administration in terms of infusion timing, cell dose and pharmacological synergism.
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Affiliation(s)
- F Locatelli
- a Department of Pediatric Hematology-Oncology , IRCCS, Bambino Gesù Children's Hospital , Rome , Italy.,b Department of Pediatrics , University of Pavia , Pavia , Italy
| | - M Algeri
- a Department of Pediatric Hematology-Oncology , IRCCS, Bambino Gesù Children's Hospital , Rome , Italy
| | - V Trevisan
- a Department of Pediatric Hematology-Oncology , IRCCS, Bambino Gesù Children's Hospital , Rome , Italy
| | - A Bertaina
- a Department of Pediatric Hematology-Oncology , IRCCS, Bambino Gesù Children's Hospital , Rome , Italy
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Schepers K, Fibbe WE. Unraveling mechanisms of mesenchymal stromal cell-mediated immunomodulation through patient monitoring and product characterization. Ann N Y Acad Sci 2015; 1370:15-23. [PMID: 26713608 DOI: 10.1111/nyas.12984] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mesenchymal stromal cells (MSCs) are increasingly used in the treatment of a variety of clinical conditions and to modulate immune responses in conditions related to auto-/alloimmunity, including graft-versus-host disease (GvHD). Although pilot data are promising, treatment responses have been highly variable, and further development of this as a therapeutic modality depends on increased insight into the properties of clinical MSC products and on understanding the mechanisms underlying responses in patients. Here we review the mechanisms that possibly underlie the capacity of MSCs to treat auto-/alloimmunity, and describe how patient monitoring can help to identify the in vivo mechanisms of action in the treatment of GvHD. Since MSCs used in the clinic originate from various donors and from a heterogeneous population of cells, we will also discuss recent insights into MSC heterogeneity and their implications for clinical MSC products. Finally, we describe a framework to improve our understanding of the efficacy and working mechanism of MSCs, which involves patient monitoring and more extensive characterization of the heterogeneity within and between different MSC preparations.
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Affiliation(s)
- Koen Schepers
- Department of Immunohematology and Blood Transfusion, Center for Stem Cell Therapy, Leiden University Medical Center, Leiden, the Netherlands
| | - Willem E Fibbe
- Department of Immunohematology and Blood Transfusion, Center for Stem Cell Therapy, Leiden University Medical Center, Leiden, the Netherlands
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Schraufstatter IU, Khaldoyanidi SK, DiScipio RG. Complement activation in the context of stem cells and tissue repair. World J Stem Cells 2015; 7:1090-1108. [PMID: 26435769 PMCID: PMC4591784 DOI: 10.4252/wjsc.v7.i8.1090] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 07/27/2015] [Indexed: 02/06/2023] Open
Abstract
The complement pathway is best known for its role in immune surveillance and inflammation. However, its ability of opsonizing and removing not only pathogens, but also necrotic and apoptotic cells, is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation, to increased survival of various cell types in the presence of split products of complement, and to the production of trophic factors by cells activated by the anaphylatoxins C3a and C5a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3a and C5a.
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Auletta JJ, Eid SK, Wuttisarnwattana P, Silva I, Metheny L, Keller MD, Guardia-Wolff R, Liu C, Wang F, Bowen T, Lee Z, Solchaga LA, Ganguly S, Tyler M, Wilson DL, Cooke KR. Human mesenchymal stromal cells attenuate graft-versus-host disease and maintain graft-versus-leukemia activity following experimental allogeneic bone marrow transplantation. Stem Cells 2015; 33:601-14. [PMID: 25336340 DOI: 10.1002/stem.1867] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 09/08/2014] [Accepted: 09/29/2014] [Indexed: 12/22/2022]
Abstract
We sought to define the effects and underlying mechanisms of human, marrow-derived mesenchymal stromal cells (hMSCs) on graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) activity. Irradiated B6D2F1 mice given C57BL/6 BM and splenic T cells and treated with hMSCs had reduced systemic GvHD, donor T-cell expansion, and serum TNFα and IFNγ levels. Bioluminescence imaging demonstrated that hMSCs redistributed from lungs to abdominal organs within 72 hours, and target tissues harvested from hMSC-treated allogeneic BMT (alloBMT) mice had less GvHD than untreated controls. Cryoimaging more precisely revealed that hMSCs preferentially distributed to splenic marginal zones and regulated T-cell expansion in the white pulp. Importantly, hMSCs had no effect on in vitro cytotoxic T-cell activity and preserved potent GvL effects in vivo. Mixed leukocyte cultures containing hMSCs exhibited decreased T-cell proliferation, reduced TNFα, IFNγ, and IL-10 but increased PGE2 levels. Indomethacin and E-prostanoid 2 (EP2) receptor antagonisms both reversed while EP2 agonism restored hMSC-mediated in vitro T-cell suppression, confirming the role for PGE2 . Furthermore, cyclo-oxygenase inhibition following alloBMT abrogated the protective effects of hMSCs. Together, our data show that hMSCs preserve GvL activity and attenuate GvHD and reveal that hMSC biodistribute to secondary lymphoid organs wherein they attenuate alloreactive T-cell proliferation likely through PGE2 induction.
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Affiliation(s)
- Jeffery J Auletta
- Host Defense Program, Hematology/Oncology/BMT and Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
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Mesenchymal Stromal Cells and Viral Infection. Stem Cells Int 2015; 2015:860950. [PMID: 26294919 PMCID: PMC4532961 DOI: 10.1155/2015/860950] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 07/08/2015] [Accepted: 07/09/2015] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal Stromal Cells (MSCs) are a subset of nonhematopoietic adult stem cells, readily isolated from various tissues and easily culture-expanded ex vivo. Intensive studies of the immune modulation and tissue regeneration over the past few years have demonstrated the great potential of MSCs for the prevention and treatment of steroid-resistant acute graft-versus-host disease (GvHD), immune-related disorders, and viral diseases. In immunocompromised individuals, the immunomodulatory activities of MSCs have raised safety concerns regarding the greater risk of primary viral infection and viral reactivation, which is a major cause of mortality after allogeneic transplantation. Moreover, high susceptibilities of MSCs to viral infections in vitro could reflect the destructive outcomes that might impair the clinical efficacy of MSCs infusion. However, the interplay between MSCs and virus is like a double-edge sword, and it also provides beneficial effects such as allowing the proliferation and function of antiviral specific effector cells instead of suppressing them, serving as an ideal tool for study of viral pathogenesis, and protecting hosts against viral challenge by using the antimicrobial activity. Here, we therefore review favorable and unfavorable consequences of MSCs and virus interaction with the highlight of safety and efficacy for applying MSCs as cell therapy.
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Mesenchymal stromal cells and hematopoietic stem cell transplantation. Immunol Lett 2015; 168:215-21. [PMID: 26116911 DOI: 10.1016/j.imlet.2015.06.013] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 06/17/2015] [Indexed: 12/18/2022]
Abstract
Mesenchymal stromal cells (MSCs) comprise a heterogeneous population of multipotent cells that can be isolated from various human tissues and culture-expanded ex vivo for clinical use. Due to their immunoregulatory properties and their ability to secrete growth factors, MSCs play a key role in the regulation of hematopoiesis and in the modulation of immune responses against allo- and autoantigens. In light of these properties, MSCs have been employed in clinical trials in the context of hematopoietic stem cell transplantation (HSCT) to facilitate engraftment of hematopoietic stem cells (HSCs) and to prevent graft failure, as well as to treat steroid-resistant acute graft-versus-host disease (GvHD). The available clinical evidence derived from these studies indicates that MSC administration is safe. Moreover, promising preliminary results in terms of efficacy have been reported in some clinical trials, especially in the treatment of acute GvHD. In this review we critically discuss recent advances in MSC therapy by reporting on the most relevant studies in the field of HSCT.
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Mesenchymal stromal cells to control donor-specific memory T cells in solid organ transplantation. Curr Opin Organ Transplant 2015; 20:79-85. [PMID: 25563995 DOI: 10.1097/mot.0000000000000145] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Mesenchymal stromal cells (MSCs) represent a promising cell therapy to promote transplant tolerance, as they influence many cells involved in immune response. Herein, we review recent evidence on the ability of MSCs to inhibit antigen-induced memory T cell response in vitro and in preclinical studies as well as immunological studies in kidney transplant recipients highlighting the effects of MSC therapy on memory CD8 T-cell proliferation and function. RECENT FINDINGS MSCs are able to inhibit in-vitro proliferation and effector functions of memory T cells in response to auto-antigen and allo-antigen stimulation. MSC infusion in animal transplant models resulted in a skew of the balance between regulatory T cells and effector/memory T cells towards a pro-tolerogenic profile. MSC in clinical transplantation is in its infancy and limited numbers of clinical studies have performed immunomonitoring of MSC-treated patients. However, available data support the capability of MSCs to control effector/memory CD8 T-cell proliferation and donor-specific CD8 T-cell function long lasting in kidney transplant setting. SUMMARY Recent studies of MSCs in kidney transplantation highlight the anticipated add-on value of the immunomodulatory properties of bone marrow derived MSCs in persistently inhibiting donor-specific effector/memory CD8 T cells, an effect not shared by the current immunosuppressive drugs.
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Mesenchymal stromal cells for prevention and treatment of graft-versus-host disease: successes and hurdles. Curr Opin Organ Transplant 2015; 20:72-8. [PMID: 25563994 DOI: 10.1097/mot.0000000000000158] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW The aim of the present review was to give a critical opinion on the use of mesenchymal stromal cells (MSCs) to treat or to prevent graft-versus-host disease (GVHD). RECENT FINDINGS The first part includes a summary of the many clinical trials published so far either to prevent or to treat GVHD in recipients of haematopoietic stem cell transplantation. We discuss in more detail a comparison in a subgroup of studies, including our own clinical work, which have in common the use of the platelet lysate to expand the MSCs from bone marrow origin.In the second part, we describe a few crucial elements of the biology of the GVHD and the biology of the MSCs themselves, showing their possible role in the immune modulation and in the inflammation in several in-vivo experimental models. SUMMARY The complexity of the clinical condition that is the object of the trials and the paucity of information on the mechanisms of action in vivo of MSCs at different anatomical sites and in different times of the development of the disease preclude at the moment the identification of a strong rationale for MSC therapeutic schedule. Moreover, the typical development of GVHD requires different time points of clinical evaluation than those previously generally utilized in studies conducted on MSCs.
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Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells. Leukemia 2015; 29:1839-46. [PMID: 25836589 DOI: 10.1038/leu.2015.89] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 03/26/2015] [Accepted: 03/30/2015] [Indexed: 01/14/2023]
Abstract
We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.
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Alimperti S, Andreadis ST. CDH2 and CDH11 act as regulators of stem cell fate decisions. Stem Cell Res 2015; 14:270-82. [PMID: 25771201 DOI: 10.1016/j.scr.2015.02.002] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 01/24/2015] [Accepted: 02/10/2015] [Indexed: 12/14/2022] Open
Abstract
Accumulating evidence suggests that the mechanical and biochemical signals originating from cell-cell adhesion are critical for stem cell lineage specification. In this review, we focus on the role of cadherin mediated signaling in development and stem cell differentiation, with emphasis on two well-known cadherins, cadherin-2 (CDH2) (N-cadherin) and cadherin-11 (CDH11) (OB-cadherin). We summarize the existing knowledge regarding the role of CDH2 and CDH11 during development and differentiation in vivo and in vitro. We also discuss engineering strategies to control stem cell fate decisions by fine-tuning the extent of cell-cell adhesion through surface chemistry and microtopology. These studies may be greatly facilitated by novel strategies that enable monitoring of stem cell specification in real time. We expect that better understanding of how intercellular adhesion signaling affects lineage specification may impact biomaterial and scaffold design to control stem cell fate decisions in three-dimensional context with potential implications for tissue engineering and regenerative medicine.
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Affiliation(s)
- Stella Alimperti
- Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Amherst, NY 14260-4200, USA
| | - Stelios T Andreadis
- Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Amherst, NY 14260-4200, USA; Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY 14203, USA.
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Abstract
In addition to their stem/progenitor properties, mesenchymal stromal cells (MSCs) possess broad immunoregulatory properties that are being investigated for potential clinical application in treating immune-based disorders. An informed view of the scope of this clinical potential will require a clear understanding of the dynamic interplay between MSCs and the innate and adaptive immune systems. In this Review, we outline current insights into the ways in which MSCs sense and control inflammation, highlighting the central role of macrophage polarization. We also draw attention to functional differences seen between vivo and in vitro contexts and between species. Finally, we discuss progress toward clinical application of MSCs, focusing on GvHD as a case study.
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Affiliation(s)
- Maria Ester Bernardo
- Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children Hospital, 00165 Rome, Italy
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Zanier ER, Pischiutta F, Riganti L, Marchesi F, Turola E, Fumagalli S, Perego C, Parotto E, Vinci P, Veglianese P, D’Amico G, Verderio C, De Simoni MG. Bone marrow mesenchymal stromal cells drive protective M2 microglia polarization after brain trauma. Neurotherapeutics 2014; 11:679-95. [PMID: 24965140 PMCID: PMC4121458 DOI: 10.1007/s13311-014-0277-y] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Microglia/macrophages (M) are major contributors to postinjury inflammation, but they may also promote brain repair in response to specific environmental signals that drive classic (M1) or alternative (M2) polarization. We investigated the activation and functional changes of M in mice with traumatic brain injuries and receiving intracerebroventricular human bone marrow mesenchymal stromal cells (MSCs) or saline infusion. MSCs upregulated Ym1 and Arginase-1 mRNA (p < 0.001), two M2 markers of protective M polarization, at 3 and 7 d postinjury, and increased the number of Ym1(+) cells at 7 d postinjury (p < 0.05). MSCs reduced the presence of the lysosomal activity marker CD68 on the membrane surface of CD11b-positive M (p < 0.05), indicating reduced phagocytosis. MSC-mediated induction of the M2 phenotype in M was associated with early and persistent recovery of neurological functions evaluated up to 35 days postinjury (p < 0.01) and reparative changes of the lesioned microenvironment. In vitro, MSCs directly counteracted the proinflammatory response of primary murine microglia stimulated by tumor necrosis factor-α + interleukin 17 or by tumor necrosis factor-α + interferon-γ and induced M2 proregenerative traits, as indicated by the downregulation of inducible nitric oxide synthase and upregulation of Ym1 and CD206 mRNA (p < 0.01). In conclusion, we found evidence that MSCs can drive the M transcriptional environment and induce the acquisition of an early, persistent M2-beneficial phenotype both in vivo and in vitro. Increased Ym1 expression together with reduced in vivo phagocytosis suggests M selection by MSCs towards the M2a subpopulation, which is involved in growth stimulation and tissue repair.
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Affiliation(s)
- Elisa R. Zanier
- />Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy
| | - Francesca Pischiutta
- />Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy
| | - Loredana Riganti
- />CNR Institute of Neuroscience, 20129 Milan, Italy
- />Department of Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy
| | - Federica Marchesi
- />Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy
| | - Elena Turola
- />CNR Institute of Neuroscience, 20129 Milan, Italy
- />Department of Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy
| | - Stefano Fumagalli
- />Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy
- />Department of Pathophysiology and Transplantation, IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Carlo Perego
- />Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy
| | - Emanuela Parotto
- />Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy
- />Institute of Anesthesia and Intensive Care, University of Padova, 35128 Padova, Italy
| | - Paola Vinci
- />Centro Ricerca Tettamanti, Clinica Pediatrica Università Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, 20900 Monza, Italy
| | - Pietro Veglianese
- />Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy
| | - Giovanna D’Amico
- />Centro Ricerca Tettamanti, Clinica Pediatrica Università Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, 20900 Monza, Italy
| | - Claudia Verderio
- />CNR Institute of Neuroscience, 20129 Milan, Italy
- />Humanitas Clinical and Research Center, 20089 Rozzano, Milan Italy
| | - Maria-Grazia De Simoni
- />Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy
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Jitschin R, Mougiakakos D, Von Bahr L, Völkl S, Moll G, Ringden O, Kiessling R, Linder S, Le Blanc K. Alterations in the cellular immune compartment of patients treated with third-party mesenchymal stromal cells following allogeneic hematopoietic stem cell transplantation. Stem Cells 2014; 31:1715-25. [PMID: 23554294 DOI: 10.1002/stem.1386] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Accepted: 03/07/2013] [Indexed: 12/14/2022]
Abstract
Adoptive transfer of third-party mesenchymal stromal cells (MSCs) has emerged as a promising tool for the treatment of steroid-refractory graft-versus-host disease (GVHD). Despite numerous in vitro studies and preclinical models, little is known about their effects on the patients' immune system. We assessed immune alterations in the T-cell, B-cell, natural killer cell, dendritic cell, and monocytic compartments of steroid-refractory GVHD patients 30, 90, and 180 days after MSC (n = 6) or placebo (n = 5) infusion, respectively. Infused MSCs were bioactive as suggested by the significant reduction in epithelial cell death, which represents a biomarker for acute GVHD. There were several indications that MSCs shift the patients' immune system toward a more tolerogenic profile. Most importantly, infusion of MSCs was associated with increased levels of regulatory (forkhead box P3 (FOXP3)(+) and interleukin (IL)-10(+) ) T-cells, reduced pro-inflammatory IL-17(+) T(Th17)-cells, and skewing toward type-2 T-helper cell responses. Furthermore, IL-2, which has been recently shown to exert a positive immune modulating effect in GVHD patients, was higher in the MSC patients at all evaluated time points during 6 months after MSC-infusion. Overall, our findings will contribute to the refinement of monitoring tools, for assessing MSC treatment-efficacy and increase our understanding regarding the MSCs' in vivo effects.
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Affiliation(s)
- Regina Jitschin
- Department of Medicine, Karolinska Institutet, Hematology Center, Karolinska University Hospital, Stockholm, Sweden.
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Griffin MD, Elliman SJ, Cahill E, English K, Ceredig R, Ritter T. Concise review: adult mesenchymal stromal cell therapy for inflammatory diseases: how well are we joining the dots? Stem Cells 2014; 31:2033-41. [PMID: 23766124 DOI: 10.1002/stem.1452] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 05/15/2013] [Accepted: 05/24/2013] [Indexed: 12/23/2022]
Abstract
Mesenchymal stromal (stem) cells (MSCs) continue to be a strong area of focus for academic- and industry-based researchers who share the goal of expanding their therapeutic use for diverse inflammatory and immune-mediated diseases. Recently, there has been an accelerated rate of scientific publication, clinical trial activity, and commercialisation in the field. This has included the reporting of exciting new developments in four areas that will be of key importance to future successful use of MSC-based therapies in large numbers of patients: (a) fundamental biology of the primary cells in bone marrow and other tissues that give rise to MSCs in culture. (b) Mechanisms by which MSCs modulate immune and inflammatory responses in vivo. (c) Insights into MSC kinetics, safety, and efficacy in relevant animal disease models. (d) Isolation, definition, and clinical trial-based testing of human MSCs by biomedical companies and academic medical centers. Despite this progress, it remains unclear whether MSCs will enter mainstream therapeutic practice as a frequently used alternative to pharmacotherapy or surgical/radiological procedures in the foreseeable future. In this review, we summarize some of the most significant new developments for each of the four areas that contribute to the process of translating MSC research to the clinical arena. In the context of this recent progress, we discuss key challenges and specific knowledge gaps which, if not addressed in a coordinated fashion, may hinder the creation of robust "translational pipelines" for consolidating the status of MSC-based therapies.
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Affiliation(s)
- Matthew D Griffin
- Regenerative Medicine Institute (REMEDI), College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
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45
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Balan A, Lucchini G, Schmidt S, Schneider A, Tramsen L, Kuçi S, Meisel R, Bader P, Lehrnbecher T. Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease--friends or foes? Leukemia 2014; 28:1941-8. [PMID: 24762460 DOI: 10.1038/leu.2014.127] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 02/22/2014] [Accepted: 03/21/2014] [Indexed: 12/29/2022]
Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells, which exhibit broad immunosuppressive activities. Moreover, they may be administered irrespectively of human leukocyte antigen (HLA) compatibility, without inducing life-threatening immunological reactions, as they express no HLA class II and limited HLA class I antigens under resting conditions. These characteristics have made MSC an appealing candidate for cell therapy after hematopoietic stem cell transplantation (HSCT), for example, for treatment of graft-versus-host disease (GvHD) or for graft rejection prevention/treatment in allogeneic HSCT recipients. Unfortunately, information regarding the effect of MSC infusion on the host response to infectious agents is scarce, and study results on infectious complications in patients receiving MSC are conflicting. The present review focuses on the available data from in vitro studies and animal models regarding the interaction of MSC with bacterial, viral and fungal pathogens. In a clinical part, we present the current information on infectious complications in allogeneic HSCT recipients who had received MSCs as prophylaxis or treatment of GvHD disease.
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Affiliation(s)
- A Balan
- 1] Department of Pediatric Hematology and Oncology, Children's Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany [2] 'Victor Babes' University of Medicine and Pharmacy, Timisoara, Romania
| | - G Lucchini
- Department of Pediatric Hematology and Oncology, Children's Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany
| | - S Schmidt
- Department of Pediatric Hematology and Oncology, Children's Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany
| | - A Schneider
- Department of Pediatric Hematology and Oncology, Children's Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany
| | - L Tramsen
- Department of Pediatric Hematology and Oncology, Children's Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany
| | - S Kuçi
- Department of Pediatric Hematology and Oncology, Children's Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany
| | - R Meisel
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Heinrich-Heine University, Düsseldorf, Germany
| | - P Bader
- Department of Pediatric Hematology and Oncology, Children's Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany
| | - T Lehrnbecher
- Department of Pediatric Hematology and Oncology, Children's Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany
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Alimperti S, Lei P, Wen Y, Tian J, Campbell AM, Andreadis ST. Serum-free spheroid suspension culture maintains mesenchymal stem cell proliferation and differentiation potential. Biotechnol Prog 2014; 30:974-83. [PMID: 24616445 DOI: 10.1002/btpr.1904] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Indexed: 02/06/2023]
Abstract
There have been many clinical trials recently using ex vivo-expanded human mesenchymal stem cells (MSCs) to treat several disease states such as graft-versus-host disease, acute myocardial infarction, Crohn's disease, and multiple sclerosis. The use of MSCs for therapy is expected to become more prevalent as clinical progress is demonstrated. However, the conventional 2-dimensional (2D) culture of MSCs is laborious and limited in scale potential. The large dosage requirement for many of the MSC-based indications further exacerbates this manufacturing challenge. In contrast, expanding MSCs as spheroids does not require a cell attachment surface and is amenable to large-scale suspension cell culture techniques, such as stirred-tank bioreactors. In the present study, we developed and optimized serum-free media for culturing MSC spheroids. We used Design of Experiment (DoE)-based strategies to systematically evaluate media mixtures and a panel of different components for effects on cell proliferation. The optimization yielded two prototype serum-free media that enabled MSCs to form aggregates and proliferate in both static and dynamic cultures. MSCs from spheroid cultures exhibited the expected immunophenotype (CD73, CD90, and CD105) and demonstrated similar or enhanced differentiation potential toward all three lineages (osteogenic, chondrogenic, adipogenic) as compared with serum-containing adherent MSC cultures. Our results suggest that serum-free media for MSC spheroids may pave the way for scale-up production of MSCs in clinically relevant manufacturing platforms such as stirred tank bioreactors.
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Affiliation(s)
- Stella Alimperti
- Bioengineering Laboratory, Dept. of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Amherst, NY, 14260-4200
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Hervy M, Weber JL, Pecheul M, Dolley-Sonneville P, Henry D, Zhou Y, Melkoumian Z. Long term expansion of bone marrow-derived hMSCs on novel synthetic microcarriers in xeno-free, defined conditions. PLoS One 2014; 9:e92120. [PMID: 24638103 PMCID: PMC3956887 DOI: 10.1371/journal.pone.0092120] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
Human mesenchymal stem cells (hMSCs) present an attractive target for cell therapy given their wide availability, immunomodulatory properties, and multipotent nature for differentiation into chondrocytes, osteocytes, and adipocytes. With the progression of hMSC clinical studies, there is an increasing demand for development of technologies that enable efficient cell scale-up into clinically relevant quantities. Commercial scale manufacturing of hMSCs will require a large surface area which is not cost effective with available two-dimensional culture vessels. Recent studies showed that microcarriers provide a three-dimensional culture environment suitable for hMSC expansion. Traditionally, biological coatings and/or serum-containing medium are required to facilitate hMSC attachment and expansion in dynamic conditions. These limitations may hinder the use of microcarriers as a scale-up technology for hMSC therapeutics, where cell products, and therefore patient safety, are more controlled with the use of xeno-free, defined culture conditions. Here we report the long term culture of hMSCs on novel synthetic Synthemax II microcarriers in two different xeno-free media. Cells were maintained over 40 days on sterile, ready-to-use microcarriers in spinner flasks with programmed agitation. hMSC expansion was obtained by addition of fresh beads without the need for enzymatic dissociation. We achieved a cumulative cell expansion of >10,000 fold, and cells retained normal hMSC phenotype, karyotype, and tri-lineage differentiation potential. To our knowledge, this report is the first example of long term culture of hMSCs on synthetic microcarriers in xeno-free, defined conditions.
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Affiliation(s)
- Martial Hervy
- Corning European Technology Center, Corning Incorporated, Avon, France
| | - Jennifer L Weber
- Corning Life Sciences Development, Corning Incorporated, Corning, New York, United States of America
| | - Marylene Pecheul
- Corning European Technology Center, Corning Incorporated, Avon, France
| | - Paula Dolley-Sonneville
- Corning Life Sciences Development, Corning Incorporated, Corning, New York, United States of America
| | - David Henry
- Corning European Technology Center, Corning Incorporated, Avon, France
| | - Yue Zhou
- Corning Life Sciences Development, Corning Incorporated, Corning, New York, United States of America
| | - Zara Melkoumian
- Corning Life Sciences Development, Corning Incorporated, Corning, New York, United States of America
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Autologous and allogeneic mesenchymal stem cells in organ transplantation: what do we know about their safety and efficacy? Curr Opin Organ Transplant 2014; 19:65-72. [PMID: 24370985 DOI: 10.1097/mot.0000000000000043] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW Recent developments toward the successful clinical application of autologous and allogeneic mesenchymal stem cells (MSCs) to organ transplantation are summarized with a focus on safety and efficacy. RECENT FINDINGS Clinical trials in organ transplantation and other conditions indicate that infusion of autologous or allogeneic MSCs is generally well tolerated. However, new studies also suggest that efficacy may be curtailed by sequestration in the lungs and early elimination. Safety concerns regarding autologous and/or allogeneic MSCs that have recently been investigated include transient proinflammatory effects, influences on opportunistic infections and cancers and alloantibody induction. Animal models indicate that autologous MSCs are likely to be efficacious in preventing or treating early intragraft inflammation and may reduce the risk of acute rejection - observations that have been borne out in a randomized controlled trial of living-donor kidney transplantation. The potential for donor-specific or third-party allogeneic MSCs to promote allograft tolerance is suggested by animal model studies but has not yet been proven in humans. SUMMARY Recent reports on the safety and efficacy of autologous MSCs for early posttransplant outcomes give cause for optimism. Benefits of allogeneic MSCs for long-term allograft survival and of MSCs for chronic transplant injury await clinical validation.
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Introna M, Lucchini G, Dander E, Galimberti S, Rovelli A, Balduzzi A, Longoni D, Pavan F, Masciocchi F, Algarotti A, Micò C, Grassi A, Deola S, Cavattoni I, Gaipa G, Belotti D, Perseghin P, Parma M, Pogliani E, Golay J, Pedrini O, Capelli C, Cortelazzo S, D'Amico G, Biondi A, Rambaldi A, Biagi E. Treatment of graft versus host disease with mesenchymal stromal cells: a phase I study on 40 adult and pediatric patients. Biol Blood Marrow Transplant 2013; 20:375-81. [PMID: 24321746 DOI: 10.1016/j.bbmt.2013.11.033] [Citation(s) in RCA: 165] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 11/30/2013] [Indexed: 02/07/2023]
Abstract
This phase I multicenter study was aimed at assessing the feasibility and safety of intravenous administration of third party bone marrow-derived mesenchymal stromal cells (MSC) expanded in platelet lysate in 40 patients (15 children and 25 adults), experiencing steroid-resistant grade II to IV graft-versus-host disease (GVHD). Patients received a median of 3 MSC infusions after having failed conventional immunosuppressive therapy. A median cell dose of 1.5 × 10(6)/kg per infusion was administered. No acute toxicity was reported. Overall, 86 adverse events and serious adverse events were reported in the study, most of which (72.1%) were of infectious nature. Overall response rate, measured at 28 days after the last MSC injection, was 67.5%, with 27.5% complete response. The latter was significantly more frequent in patients exhibiting grade II GVHD as compared with higher grades (61.5% versus 11.1%, P = .002) and was borderline significant in children as compared with adults (46.7 versus 16.0%, P = .065). Overall survival at 1 and 2 years from the first MSC administration was 50.0% and 38.6%, with a median survival time of 1.1 years. In conclusion, MSC can be safely administered on top of conventional immunosuppression for steroid resistant GVHD treatment. Eudract Number 2008-007869-23, NCT01764100.
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Affiliation(s)
- Martino Introna
- Division of Hematology and Laboratory of Cell Therapy "G. Lanzani", Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
| | - Giovanna Lucchini
- HSCT Pediatric Unit and Laboratory of Cell Therapy "S. Verri", San Gerardo Hospital, Monza, Italy
| | - Erica Dander
- HSCT Pediatric Unit, "M. Tettamanti" Research Centre, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Stefania Galimberti
- Department of Health Sciences, Center of Biostatistics for Clinical Epidemiology, University of Milan-Bicocca, Monza, Italy
| | - Attilio Rovelli
- HSCT Pediatric Unit and Laboratory of Cell Therapy "S. Verri", San Gerardo Hospital, Monza, Italy
| | - Adriana Balduzzi
- HSCT Pediatric Unit and Laboratory of Cell Therapy "S. Verri", San Gerardo Hospital, Monza, Italy
| | - Daniela Longoni
- HSCT Pediatric Unit and Laboratory of Cell Therapy "S. Verri", San Gerardo Hospital, Monza, Italy
| | - Fabio Pavan
- HSCT Pediatric Unit and Laboratory of Cell Therapy "S. Verri", San Gerardo Hospital, Monza, Italy
| | - Francesca Masciocchi
- HSCT Pediatric Unit and Laboratory of Cell Therapy "S. Verri", San Gerardo Hospital, Monza, Italy
| | - Alessandra Algarotti
- Division of Hematology and Laboratory of Cell Therapy "G. Lanzani", Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Caterina Micò
- Division of Hematology and Laboratory of Cell Therapy "G. Lanzani", Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Anna Grassi
- Division of Hematology and Laboratory of Cell Therapy "G. Lanzani", Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Sara Deola
- Divisione di Ematologia e TMO, Ospedale Generale di Bolzano, Bolzano, Italy
| | - Irene Cavattoni
- Divisione di Ematologia e TMO, Ospedale Generale di Bolzano, Bolzano, Italy
| | - Giuseppe Gaipa
- HSCT Pediatric Unit and Laboratory of Cell Therapy "S. Verri", San Gerardo Hospital, Monza, Italy
| | - Daniela Belotti
- HSCT Pediatric Unit and Laboratory of Cell Therapy "S. Verri", San Gerardo Hospital, Monza, Italy
| | | | - Matteo Parma
- HSCT Adult Unit, San Gerardo Hospital, Monza, Italy
| | | | - Josee Golay
- Division of Hematology and Laboratory of Cell Therapy "G. Lanzani", Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Olga Pedrini
- Division of Hematology and Laboratory of Cell Therapy "G. Lanzani", Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Chiara Capelli
- Division of Hematology and Laboratory of Cell Therapy "G. Lanzani", Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Sergio Cortelazzo
- Divisione di Ematologia e TMO, Ospedale Generale di Bolzano, Bolzano, Italy
| | - Giovanna D'Amico
- HSCT Pediatric Unit, "M. Tettamanti" Research Centre, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Andrea Biondi
- HSCT Pediatric Unit and Laboratory of Cell Therapy "S. Verri", San Gerardo Hospital, Monza, Italy
| | - Alessandro Rambaldi
- Division of Hematology and Laboratory of Cell Therapy "G. Lanzani", Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Ettore Biagi
- HSCT Pediatric Unit and Laboratory of Cell Therapy "S. Verri", San Gerardo Hospital, Monza, Italy
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Conforti A, Biagini S, Del Bufalo F, Sirleto P, Angioni A, Starc N, Li Pira G, Moretta F, Proia A, Contoli B, Genovese S, Ciardi C, Avanzini MA, Rosti V, Lo-Coco F, Locatelli F, Bernardo ME. Biological, functional and genetic characterization of bone marrow-derived mesenchymal stromal cells from pediatric patients affected by acute lymphoblastic leukemia. PLoS One 2013; 8:e76989. [PMID: 24244271 PMCID: PMC3820675 DOI: 10.1371/journal.pone.0076989] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 09/04/2013] [Indexed: 02/04/2023] Open
Abstract
Alterations in hematopoietic microenvironment of acute lymphoblastic leukemia patients have been claimed to occur, but little is known about the components of marrow stroma in these patients. In this study, we characterized mesenchymal stromal cells (MSCs) isolated from bone marrow (BM) of 45 pediatric patients with acute lymphoblastic leukemia (ALL-MSCs) at diagnosis (day+0) and during chemotherapy treatment (days: +15; +33; +78), the time points being chosen according to the schedule of BM aspirates required by the AIEOP-BFM ALL 2009 treatment protocol. Morphology, proliferative capacity, immunophenotype, differentiation potential, immunomodulatory properties and ability to support long-term hematopoiesis of ALL-MSCs were analysed and compared with those from 41 healthy donors (HD-MSCs). ALL-MSCs were also genetically characterized through array-CGH, conventional karyotyping and FISH analysis. Moreover, we compared ALL-MSCs generated at day+0 with those isolated during chemotherapy. Morphology, immunophenotype, differentiation potential and in vitro life-span did not differ between ALL-MSCs and HD-MSCs. ALL-MSCs showed significantly lower proliferative capacity (p<0.001) and ability to support in vitro hematopoiesis (p = 0.04) as compared with HD-MSCs, while they had similar capacity to inhibit in vitro mitogen-induced T-cell proliferation (p = N.S.). ALL-MSCs showed neither the typical translocations carried by the leukemic clone (when present), nor other genetic abnormalities acquired during ex vivo culture. Our findings indicate that ALL-MSCs display reduced ability to proliferate and to support long-term hematopoiesis in vitro. ALL-MSCs isolated at diagnosis do not differ from those obtained during treatment.
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Affiliation(s)
- Antonella Conforti
- Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
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