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Theil F, Kuckhahn A, Hörning A, Völkl S, Knab K, Fritz N, Gräbner C, Ramsperger-Gleixner M, Weyand M, Heim C. Repeated CXCR4 Blockade by Plerixafor Attenuates Transplant Vasculopathy in Murine Aortic Allografts. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:1542-1552. [PMID: 39382301 DOI: 10.4049/jimmunol.2300632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 09/18/2024] [Indexed: 10/10/2024]
Abstract
Plerixafor, a hematopoietic stem cell mobilization agent, increases the peripheral blood content of effector and regulatory T cells and may have beneficial effects on cardiac allograft vasculopathy. The aim of the current study was to evaluate its effects in a murine aortic allograft model using different application procedures. Allogeneic donor aorta grafts (n = 8/group) from C57BL/6 mice(H2b) were abdominally transplanted into CBA mice (H2k). Plerixafor application was performed either continuously for 14 d using abdominally implanted osmotic pumps (1 mg/kg/d) or i.p. with a single dose (1 and 5 mg/kg) on day 0 or pulsed injections of 1 mg/kg on days 0, 7, 14, and 21. Cell distribution was monitored by FACS. Aortic grafts were evaluated for neointima development by Elastica-van-Gieson on day 30. Immunofluorescence and intragraft gene expression analysis were performed. On day 14, significantly fewer hematopoietic stem cells were found in the bone marrow of all plerixafor-treated mice. In the pulsed application group, significantly more hematopoietic stem cells were found in the peripheral blood on day 14 (0.045 ± 0.002%; p < 0.01 [pulsed]; versus 0.0068 ± 0.002% [control]) and also more regulatory T cells. PCR revealed lower inflammatory cytokines. The luminal occlusion was significantly reduced in the pulsed treated group (33.65 ± 8.84 versus 53.13 ± 12.41) going along with decreased neointimal CD4+ T cell and plasmacytoid dendritic cell infiltration, as well as less smooth muscle cell proliferation. The application of plerixafor attenuates chronic rejection in aortic allografts via immunomodulatory effects. Injection of repeated low-dose plerixafor is the most effective application form in the aortic transplant model.
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Affiliation(s)
- Frank Theil
- Department of Cardiac Surgery, Universitätsklinikum Erlangen, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Annika Kuckhahn
- Department of Cardiac Surgery, Universitätsklinikum Erlangen, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - André Hörning
- Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Department of Pediatric and Adolescent Medicine, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Simon Völkl
- Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Department of Internal Medicine 5 - Hematology and Oncology, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Katharina Knab
- Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Niklas Fritz
- Department of Cardiac Surgery, Universitätsklinikum Erlangen, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Cindy Gräbner
- Department of Cardiac Surgery, Universitätsklinikum Erlangen, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Martina Ramsperger-Gleixner
- Department of Cardiac Surgery, Universitätsklinikum Erlangen, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Michael Weyand
- Department of Cardiac Surgery, Universitätsklinikum Erlangen, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Christian Heim
- Department of Cardiac Surgery, Universitätsklinikum Erlangen, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Department for Cardiac and Vascular Surgery, Medizincampus Oberfranken, Bayreuth, Germany
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Hernandez Pichardo A, Wilm B, Liptrott NJ, Murray P. Intravenous Administration of Human Umbilical Cord Mesenchymal Stromal Cells Leads to an Inflammatory Response in the Lung. Stem Cells Int 2023; 2023:7397819. [PMID: 37705699 PMCID: PMC10497368 DOI: 10.1155/2023/7397819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 06/25/2023] [Accepted: 08/04/2023] [Indexed: 09/15/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) administered intravenously (IV) have shown efficacy in preclinical models of various diseases. This is despite the cells not reaching the site of injury due to entrapment in the lungs. The immunomodulatory properties of MSCs are thought to underlie their therapeutic effects, irrespective of whether they are sourced from bone marrow, adipose tissue, or umbilical cord. To better understand how MSCs affect innate immune cell populations in the lung, we evaluated the distribution and phenotype of neutrophils, monocytes, and macrophages by flow cytometry and histological analyses after delivering human umbilical cord-derived MSCs (hUC-MSCs) IV into immunocompetent mice. After 2 hr, we observed a significant increase in neutrophils, and proinflammatory monocytes and macrophages. Moreover, these immune cells localized in close proximity to the MSCs, suggesting an active role in their clearance. By 24 hr, we detected an increase in anti-inflammatory monocytes and macrophages. These results suggest that the IV injection of hUC-MSCs leads to an initial inflammatory phase in the lung shortly after injection, followed by a resolution phase 24 hr later.
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Affiliation(s)
- Alejandra Hernandez Pichardo
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
- Centre for Pre-Clinical Imaging, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Bettina Wilm
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
- Centre for Pre-Clinical Imaging, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Neill J. Liptrott
- Immunocompatibility Group, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Patricia Murray
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
- Centre for Pre-Clinical Imaging, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
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Wu Z, Liang J, Huang W, Jiang L, Paul C, Gao X, Alam P, Kanisicak O, Xu M, Wang Y. Immunomodulatory effects of mesenchymal stem cells for the treatment of cardiac allograft rejection. Exp Biol Med (Maywood) 2020; 246:851-860. [PMID: 33327780 DOI: 10.1177/1535370220978650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Heart transplantation continues to be the gold standard clinical intervention to treat patients with end-stage heart failure. However, there are major complications associated with this surgical procedure that reduce the survival prognosis of heart transplant patients, including allograft rejection, malignancies, infections, and other complications that arise from the use of broad-spectrum immunosuppression drugs. Recent studies have demonstrated the use of mesenchymal stem cells (MSCs) against allotransplantation rejection in both in vitro and in vivo settings due to their immunomodulatory properties. Therefore, utilization of MSCs provides new and exciting strategies to improve heart transplantation and potentially reduce the use of broad-spectrum immunosuppression drugs while alleviating allograft rejection. In this review, we will discuss the current research on the mechanisms of cardiac allograft rejection, the physiological and immunological characteristics of MSCs, the effects of MSCs on the immune system, and immunomodulation of heart transplantation by MSCs.
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Affiliation(s)
- Zhichao Wu
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Jialiang Liang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Wei Huang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Lin Jiang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Christian Paul
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Xiang Gao
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Perwez Alam
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Onur Kanisicak
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Meifeng Xu
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
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Mirershadi F, Ahmadi M, Rezabakhsh A, Rajabi H, Rahbarghazi R, Keyhanmanesh R. Unraveling the therapeutic effects of mesenchymal stem cells in asthma. Stem Cell Res Ther 2020; 11:400. [PMID: 32933587 PMCID: PMC7493154 DOI: 10.1186/s13287-020-01921-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/27/2020] [Accepted: 09/02/2020] [Indexed: 12/13/2022] Open
Abstract
Asthma is a chronic inflammatory disease associated with airway hyper-responsiveness, chronic inflammatory response, and excessive structural remodeling. The current therapeutic strategies in asthmatic patients are based on controlling the activity of type 2 T helper lymphocytes in the pulmonary tissue. However, most of the available therapies are symptomatic and expensive and with diverse side outcomes in which the interruption of these modalities contributes to the relapse of asthmatic symptoms. Up to date, different reports highlighted the advantages and beneficial outcomes regarding the transplantation of different stem cell sources, and relevant products from for the diseases' alleviation and restoration of injured sites. However, efforts to better understand by which these cells elicit therapeutic effects are already underway. The precise understanding of these mechanisms will help us to translate stem cells into the clinical setting. In this review article, we described current knowledge and future perspectives related to the therapeutic application of stem cell-based therapy in animal models of asthma, with emphasis on the underlying therapeutic mechanisms.
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Affiliation(s)
- Fatemeh Mirershadi
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Daneshgah St, Tabriz, 51666-14766, Iran.,Department of Physiology, Ardabil Branch, Islamic Azad University, Ardabil, Iran
| | - Mahdi Ahmadi
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Daneshgah St, Tabriz, 51666-14766, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Rajabi
- Koc University Research Center for Translational Medicine (KUTTAM), Koc University School of Medicine, Istanbul, Turkey.,Department of Pulmonary Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Daneshgah St, Tabriz, 51548-53431, Iran.
| | - Rana Keyhanmanesh
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Daneshgah St, Tabriz, 51666-14766, Iran. .,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Cyclosporine A promotes the therapeutic effect of mesenchymal stem cells on transplantation reaction. Clin Sci (Lond) 2020; 133:2143-2157. [PMID: 31654074 DOI: 10.1042/cs20190294] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 10/15/2019] [Accepted: 10/17/2019] [Indexed: 12/15/2022]
Abstract
The successful application of mesenchymal stem cells (MSCs) remains a major challenge in stem cell therapy. Currently, several in vitro studies have indicated potentially beneficial interactions of MSCs with immunosuppressive drugs. These interactions can be even more complex in vivo, and it is in this setting that we investigate the effect of MSCs in combination with Cyclosporine A (CsA) on transplantation reaction and allogeneic cell survival. Using an in vivo mouse model, we found that CsA significantly promoted the survival of MSCs in various organs and tissues of the recipients. In addition, compared to treatment with CsA or MSCs alone, the survival of transplanted allogeneic cells was significantly improved after the combined application of MSCs with CsA. We further observed that the combinatory treatment suppressed immune response to the alloantigen challenge and modulated the immune balance by harnessing proinflammatory CD4+T-bet+ and CD4+RORγt+ cell subsets. These changes were accompanied by a significant decrease in IL-17 production along with an elevated level of IL-10. Co-cultivation of purified naive CD4+ cells with peritoneal macrophages isolated from mice treated with MSCs and CsA revealed that MSC-educated macrophages play an important role in the immunomodulatory effect observed on distinct T-cell subpopulations. Taken together, our findings suggest that CsA promotes MSC survival in vivo and that the therapeutic efficacy of the combination of MSCs with CsA is superior to each monotherapy. This combinatory treatment thus represents a promising approach to reducing immunosuppressant dosage while maintaining or even improving the outcome of therapy.
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Li H, Qian F, Liu H, Zhang Z. Elevated Uric Acid Levels Promote Vascular Smooth Muscle Cells (VSMC) Proliferation via an Nod-Like Receptor Protein 3 (NLRP3)-Inflammasome-Dependent Mechanism. Med Sci Monit 2019; 25:8457-8464. [PMID: 31707403 PMCID: PMC6865250 DOI: 10.12659/msm.916667] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 07/10/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hyperuricemia has a pathogenic role in the development of hypertension and other cardiovascular diseases (CVD). Uric acid has been reported to activate Nod-like receptor protein 3 (NLRP3)-inflammasome and alter vascular smooth muscle cells (VSMC). However, the potential mechanisms underlying this association are still not understood. The aim of this study was to investigate the role and potential mechanisms of uric acid in proliferation of VSMC. MATERIAL AND METHODS Cell Counting Kit-8 (CCK-8) proliferation assay and colony formation assay were performed to determine the proliferative ability of VSMC under uric acid stimulation. Immunofluorescence microscopy was carried out to determine the expression of Alpha-smooth muscle actin (alpha-SMA). In addition, real-time PCR and Western blot were used to detect the expression of NLRP3-inflammasome, and ELISA was performed to measure the levels of IL-18 and IL-1ß. RESULTS The results showed that uric acid increases the proliferation of VSMC and induces alpha-SMA accumulation. We also found that uric acid increases the level of NLRP3 and induces NLRP3-inflammasome activation. The expressions of uric acid-induced inflammatory markers IL-1ß and IL-18 were decreased by the inhibitor MCC950. CONCLUSIONS Our findings revealed that uric acid induces inflammation through NLRP3-inflammasome-mediated VSMC proliferation. NLRP3 may be a new therapeutic target for hypertension.
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Affiliation(s)
- Hui Li
- Department of Cardiology, Lu’an People’s Hospital, Lu’an, Anhui, P.R. China
| | - Fudong Qian
- Department of Cardiology, Lu’an People’s Hospital, Lu’an, Anhui, P.R. China
| | - Heyu Liu
- Department of Cardiology, Lu’an People’s Hospital, Lu’an, Anhui, P.R. China
| | - Zhiyong Zhang
- Department of Cardiology, Suqian First Hospital, Suqian Branch of Jiangsu Province Hospital, Suqian, Jiangsu, P.R. China
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Weiss ARR, Dahlke MH. Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs. Front Immunol 2019; 10:1191. [PMID: 31214172 PMCID: PMC6557979 DOI: 10.3389/fimmu.2019.01191] [Citation(s) in RCA: 477] [Impact Index Per Article: 79.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 05/10/2019] [Indexed: 12/13/2022] Open
Abstract
Expectations on mesenchymal stem cell (MSC) treatment are high, especially in the fields of sepsis, transplant medicine, and autoimmune diseases. Various pre-clinical studies have been conducted with encouraging results, although the mechanisms of action behind the observed immunomodulatory capacity of mesenchymal stem cells have not been fully understood. Previous studies have demonstrated that the immunomodulatory effect of MSCs is communicated via MSC-secreted cytokines and has been proven to rely on the local microenvironment as some of the observed effects depend on a pre-treatment of MSCs with inflammatory cytokines. Nonetheless, recent findings indicate that the cytokine-mediated effects are only one part of the equation as apoptotic, metabolically inactivated, or even fragmented MSCs have been shown to possess an immunomodulatory potential as well. Both cytokine-dependent and cytokine-independent mechanisms suggest a key role for regulatory T cells and monocytes in the overall pattern, but the principle as to why viable and non-viable MSCs have similar immunomodulatory capacities remains elusive. Here we review the current knowledge on cellular and molecular mechanisms involved in MSC-mediated immunomodulation and focus on the viability of MSCs, as there is still uncertainty concerning the tumorigenic potential of living MSCs.
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CXCR4 Antagonist Reduced the Incidence of Acute Rejection and Controlled Cardiac Allograft Vasculopathy in a Swine Heart Transplant Model Receiving a Mycophenolate-based Immunosuppressive Regimen. Transplantation 2019; 102:2002-2011. [PMID: 30095739 PMCID: PMC6257103 DOI: 10.1097/tp.0000000000002404] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND CXC motif chemokine receptor 4 (CXCR4) blockade is pursued as an alternative to mesenchymal stem cell treatment in transplantation based on our previous report that burixafor, through CXCR4 antagonism, mobilizes immunomodulatory mesenchymal stem cells. Here, we explored the efficacy of combining mycophenolate mofetil (MMF)-based immunosuppressants with repetitive burixafor administration. METHODS Swine heterotopic cardiac allograft recipients received MMF and corticosteroids (control, n = 10) combined with burixafor as a 2-dose (burixafor2D, n = 7) or 2-dose plus booster injections (burixafor2D + B, n = 5) regimen. The efficacy endpoints were graft survival, freedom from first acute rejection, and the severity of intimal hyperplasia. Each specimen was sacrificed either at its first graft arrest or after 150 days. RESULTS After 150 days, all specimens in the control group had died, but 28.5% of the burixafor2D group survived, and 60% of the burixafor2D + B group survived (P = 0.0088). Although the control group demonstrated acute rejection at a median of 33.5 days, the burixafor2D + B group survived without acute rejection for a median of 136 days (P = 0.0209). Burixafor administration significantly attenuated the incidence rate of acute rejection (P = 0.002) and the severity of intimal hyperplasia (P = 0.0097) at end point relative to the controls. These findings were associated with reduced cell infiltrates in the allografts, and modulation of C-reactive protein profiles in the circulation. CONCLUSIONS The augmentation of conventional MMF plus corticosteroids with a CXCR4 antagonist is potentially effective in improving outcomes after heart transplantation in minipigs. Future studies are warranted into optimizing the therapeutic regimens for humans.
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Erpicum P, Weekers L, Detry O, Bonvoisin C, Delbouille MH, Grégoire C, Baudoux E, Briquet A, Lechanteur C, Maggipinto G, Somja J, Pottel H, Baron F, Jouret F, Beguin Y. Infusion of third-party mesenchymal stromal cells after kidney transplantation: a phase I-II, open-label, clinical study. Kidney Int 2019; 95:693-707. [DOI: 10.1016/j.kint.2018.08.046] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 07/25/2018] [Accepted: 08/23/2018] [Indexed: 02/08/2023]
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Casiraghi F, Perico N, Remuzzi G. Mesenchymal stromal cells for tolerance induction in organ transplantation. Hum Immunol 2017; 79:304-313. [PMID: 29288697 DOI: 10.1016/j.humimm.2017.12.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 12/06/2017] [Accepted: 12/18/2017] [Indexed: 12/20/2022]
Abstract
The primary challenge in organ transplantation continues to be the need to suppress the host immune system long-term to ensure prolonged allograft survival. Long-term non-specific immunosuppression can, however, result in life-threatening complications. Thus, efforts have been pursued to explore novel strategies that would allow minimization of maintenance immunosuppression, eventually leading to transplant tolerance. In this scenario, bone marrow-derived mesenchymal stromal cells (MSC), given their unique immunomodulatory properties to skew the balance between regulatory and memory T cells, have emerged as potential candidates for cell-based therapy to promote immune tolerance. Here, we review our initial clinical experience with bone marrow-derived MSC in living-donor kidney transplant recipients and provide an overview of the available results of other clinical programs with MSC in kidney and liver transplantation, highlighting hurdles and success of this innovative cell-based therapy.
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Affiliation(s)
| | - Norberto Perico
- IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
| | - Giuseppe Remuzzi
- IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale (ASST), Papa Giovanni XXIII, Bergamo, Italy; L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
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Mohammadi Ayenehdeh J, Niknam B, Rasouli S, Hashemi SM, Rahavi H, Rezaei N, Soleimani M, Liaeiha A, Niknam MH, Tajik N. Immunomodulatory and protective effects of adipose tissue-derived mesenchymal stem cells in an allograft islet composite transplantation for experimental autoimmune type 1 diabetes. Immunol Lett 2017; 188:21-31. [PMID: 28506774 DOI: 10.1016/j.imlet.2017.05.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 05/05/2017] [Indexed: 01/01/2023]
Abstract
BACKGROUND Allogeneic islet transplantation could be an ideal alternative therapy for Type 1 Diabetes Mellitus (T1DM). Adipose Tissue-derived Mesenchymal Stem Cells (AT-MSCs) characterized by immunomodulatory and protective effects may have the potential to improve the outcome of this highly immunogenic transplant. METHODS Syngenic AT-MSCs along with allograft islets embedded in hydrogelic composite and transplanted intraperitoneally in Streptozotocin (STZ) induced diabetic C57BL/6 mice. RESULTS In vitro experiments of co-imbedded islets and AT-MSCs in a hydrogel revealed AT-MSCs are able to significantly increase insulin secretion. During a 32 days of post-transplant period, blood glucose monitoring showed a decrease from over 400mg/dl to less than 150mg/dl and at the end of 32 days, mice have been dissected and assessed. Graft histopathology demonstrated that hydrogel makes an artificial immune isolation site and AT-MSCs contribute greatly to the reduction of the immune cells infiltration. Analyses of mononuclear cells isolated from Mesenteric Lymph Nodes (MLNs) and spleen showed that AT-MSCs co-transplanted with allograft decreased pro-inflammatory cytokines and increased regulatory cytokines (for both MLNs and spleen) and regulatory T cells (Treg) population (only for MLNs). In addition, real time-PCR assays revealed that transcript levels of IDO, iNOS, and PDX1, significantly increased in allograft islets in the presence of AT-MSCs. CONCLUSIONS according to results, this investigation indicates that AT-MSCs can be regarded as promising complementary candidates for engineered-cell therapy using hydrogel composites in islet transplantation.
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Affiliation(s)
- Jamal Mohammadi Ayenehdeh
- Immunology Research Center (IRC), Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahare Niknam
- Immunology Research Center (IRC), Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Shima Rasouli
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Rahavi
- Immunology Research Center (IRC), Iran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Stem Cell Biology, Stem Cell Technology Research Center, Tehran, Iran
| | - Ali Liaeiha
- Immunology Research Center (IRC), Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Niknam
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nader Tajik
- Immunology Research Center (IRC), Iran University of Medical Sciences, Tehran, Iran.
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da Silva MB, da Cunha FF, Terra FF, Camara NOS. Old game, new players: Linking classical theories to new trends in transplant immunology. World J Transplant 2017; 7:1-25. [PMID: 28280691 PMCID: PMC5324024 DOI: 10.5500/wjt.v7.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/16/2016] [Accepted: 12/07/2016] [Indexed: 02/05/2023] Open
Abstract
The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.
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Carty F, Mahon BP, English K. The influence of macrophages on mesenchymal stromal cell therapy: passive or aggressive agents? Clin Exp Immunol 2017; 188:1-11. [PMID: 28108980 DOI: 10.1111/cei.12929] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 01/16/2017] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stromal cells (MSC) have emerged as promising cell therapies for multiple conditions based on demonstrations of their potent immunomodulatory and regenerative capacities in models of inflammatory disease. Understanding the effects of MSC on T cells has dominated the majority of work carried out in this field to date; recently, however, a number of studies have shown that the therapeutic effect of MSC requires the presence of macrophages. It is timely to review the mechanisms and manner by which MSC modulate macrophage populations in order to design more effective MSC therapies and clinical studies. A complex cross-talk exists through which MSC and macrophages communicate, a communication that is not controlled exclusively by MSC. Here, we examine the evidence that suggests that MSC not only respond to inflammatory macrophages and adjust their secretome accordingly, but also that macrophages respond to encounters with MSC, creating a feedback loop which contributes to the immune regulation observed following MSC therapy. Future studies examining the effects of MSC on macrophages should consider the antagonistic role that macrophages play in this exchange.
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Affiliation(s)
- F Carty
- Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland
| | - B P Mahon
- Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland
| | - K English
- Institute of Immunology, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland
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Grégoire C, Lechanteur C, Briquet A, Baudoux É, Baron F, Louis E, Beguin Y. Review article: mesenchymal stromal cell therapy for inflammatory bowel diseases. Aliment Pharmacol Ther 2017; 45:205-221. [PMID: 27878827 DOI: 10.1111/apt.13864] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 06/21/2016] [Accepted: 10/25/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are chronic relapsing diseases in which pro-inflammatory immune cells and cytokines induce intestinal tissue damage and disability. Mesenchymal stromal cells (MSCs) exert powerful immunomodulatory effects and stimulate tissue repair. AIM To review the current data on mesenchymal stromal cell therapy in IBD. METHOD We searched PubMed and 'ClinicalTrials.gov' databases using the terms 'mesenchymal stromal cells', 'mesenchymal stem cell transplantation', 'inflammatory bowel diseases', 'Crohn disease' and 'colitis, ulcerative'. Additional publications were identified from individual article reference lists. RESULTS MSCs include inhibition of Th1/Th17 lymphocytes and recruitment of regulatory T lymphocytes, induction of antigen-presenting cells into a regulatory-like profile, and stimulation of epithelial cell differentiation and proliferation. More than 200 patients with refractory fistulas have been treated with local injections of MSCs, resulting in complete response in more than half, and in overall response in approximately two thirds of patients. In refractory luminal Crohn's disease, 49 cases of systemic MSC infusions have been reported, while trials with autologous MSCs resulted in mitigated responses, studies using allogeneic MSCs were promising, with around 60% of patients experiencing a response and around 40% achieving clinical remission. CONCLUSIONS Mesenchymal stromal cells might represent a promising therapy for IBD, especially for Crohn's disease. There remain many unsolved questions concerning the optimal origin and source of mesenchymal stromal cells, dosage and modalities of administration. Moreover, mesenchymal stromal cells still need to prove their effectiveness compared with conventional treatments in randomised controlled trials.
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Affiliation(s)
- C Grégoire
- Unit of Haematology, Department of Haematology, CHU of Liège, GIGA-I3, University of Liège, Liège, Belgium
| | - C Lechanteur
- Laboratory of Cell and Gene Therapy (LTCG), CHU of Liège, Liège, Belgium
| | - A Briquet
- Laboratory of Cell and Gene Therapy (LTCG), CHU of Liège, Liège, Belgium
| | - É Baudoux
- Laboratory of Cell and Gene Therapy (LTCG), CHU of Liège, Liège, Belgium
| | - F Baron
- Unit of Haematology, Department of Haematology, CHU of Liège, GIGA-I3, University of Liège, Liège, Belgium
| | - E Louis
- Department of Gastroenterology, CHU of Liège, University of Liège, Liège, Belgium
| | - Y Beguin
- Unit of Haematology, Department of Haematology, CHU of Liège, GIGA-I3, University of Liège, Liège, Belgium.,Laboratory of Cell and Gene Therapy (LTCG), CHU of Liège, Liège, Belgium
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16
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Mesenchymal stromal cells for immunoregulation after liver transplantation. Curr Opin Organ Transplant 2016; 21:541-549. [DOI: 10.1097/mot.0000000000000361] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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17
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The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients. Transplantation 2016; 100:39-53. [PMID: 26680372 PMCID: PMC4683034 DOI: 10.1097/tp.0000000000000869] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.
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Premise and promise of mesenchymal stem cell-based therapies in clinical vascularized composite allotransplantation. Curr Opin Organ Transplant 2016; 20:608-14. [PMID: 26536421 DOI: 10.1097/mot.0000000000000247] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Over the past decade, clinical vascularized composite allotransplantation (VCA) has enabled functional and quality of life restoration in a wide range of indications secondary to devastating tissue loss. However, the spectre of toxicity and long-term complications of chronic immunosuppression has curtailed the momentum of VCA. This study summarizes the literature evidence behind successful mesenchymal stem cell (MSC)-based cell therapies highlighting their multipronged immunomodulatory, restorative and regenerative characteristics with special emphasis towards VCA applications. RECENT FINDINGS Experimental and clinical studies in solid organs and VCA have confirmed that MSCs facilitate immunosuppression-free allograft survival or tolerance, stimulate peripheral nerve regeneration, attenuate ischaemia-reperfusion injury, and improve tissue healing after surgery. It has been hypothesized that MSC-induced long-term operational tolerance in experimental VCA is mediated by induction of mixed donor-specific chimerism and regulatory T-cell mechanisms. All these characteristics of MSCs could thus help expand the scope and clinical feasibility of VCA. SUMMARY Cellular therapies, especially those focusing on MSCs, are emerging in solid organ transplantation including VCA. Although some clinical trials have begun to assess the effects of MSCs in solid organ transplantation, much scientific domain remains uncharted, especially for VCA.
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Zhu X, Guo J, He C, Geng H, Yu G, Li J, Zheng H, Ji X, Yan F. Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles. Sci Rep 2016; 6:21683. [PMID: 26899550 PMCID: PMC4761943 DOI: 10.1038/srep21683] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 01/27/2016] [Indexed: 11/13/2022] Open
Abstract
Paclitaxel (PTX) has been recognized as a promising drug for intervention of vascular reconstructions. However, it is still difficult to achieve local drug delivery in a spatio-temporally controllable manner under real-time image guidance. Here, we introduce an ultrasound (US) triggered image-guided drug delivery approach to inhibit vascular reconstruction via paclitaxel (PTX)-loaded microbubbles (PLM) in a rabbit iliac balloon injury model. PLM was prepared through encapsulating PTX in the shell of lipid microbubbles via film hydration and mechanical vibration technique. Our results showed PLM could effectively deliver PTX when exposed to US irradiation and result in significantly lower viability of vascular smooth muscle cells. Ultrasonographic examinations revealed the US signals from PLM in the iliac artery were greatly increased after intravenous administration of PLM, making it possible to identify the restenosis regions of iliac artery. The in vivo anti-restenosis experiments with PLM and US greatly inhibited neointimal hyperplasia at the injured site, showing an increased lumen area and reduced the ratio of intima area and the media area (I/M ratio). No obvious functional damages to liver and kidney were observed for those animals. Our study provided a promising approach to realize US triggered image-guided PTX delivery for therapeutic applications against iliac restenosis.
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Affiliation(s)
- Xu Zhu
- Department of Cardiology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Jun Guo
- Department of Cardiology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Department of Pediatrics, Mianyang Central Hospital, Mianyang, Sichuan, China
| | - Cancan He
- Department of Cardiology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Huaxiao Geng
- Department of Cardiology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Gengsheng Yu
- Department of Cardiology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Jinqing Li
- Department of Radiology, 324 Hospital of the PLA, Chongqing, China
| | - Hairong Zheng
- Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Shenzhen Key Laboratory of Nanobiomechanics, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Xiaojuan Ji
- Department of Cardiology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Fei Yan
- Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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Ren S, Hu J, Chen Y, Yuan T, Hu H, Li S. Human umbilical cord derived mesenchymal stem cells promote interleukin-17 production from human peripheral blood mononuclear cells of healthy donors and systemic lupus erythematosus patients. Clin Exp Immunol 2015; 183:389-96. [PMID: 26507122 DOI: 10.1111/cei.12737] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2015] [Indexed: 01/14/2023] Open
Abstract
Inflammation instigated by interleukin (IL)-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. The expansion of IL-17-producing cells from healthy donors is reportedly promoted by mesenchymal stem cells derived from fetal bone marrow. In the present study, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were examined for their effects on lymphocytes from healthy donors and from patients with systemic lupus erythematosus (SLE). Significantly higher levels of IL-17 were produced when CD4(+) T cells from healthy donors were co-cultured with hUC-MSCs than those that were cultured alone. Blocking experiments identified that this effect might be mediated partially through prostaglandin E2 (PGE2 ) and IL-1β, without IL-23 involvement. We then co-cultured hUC-MSCs with human CD4(+) T cells from systemic lupus erythematosus patients. Ex-vivo inductions of IL-17 by hUC-MSCs in stimulated lymphocytes were significantly higher in SLE patients than in healthy donors. This effect was not observed for IL-23. Taken together, our results represent that hUC-MSCs can promote the IL-17 production from CD4(+) T cells in both healthy donor and SLE patients. PGE2 and IL-1β might also be partially involved in the promotive effect of hUC-MSCs.
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Affiliation(s)
- S Ren
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - J Hu
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - Y Chen
- Department of Hepatobiliary Surgery, General Hospital of Beijing Military Area Command, Beijing, China
| | - T Yuan
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - H Hu
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - S Li
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Ministry of Education, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China
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Padda J, Sequiera GL, Sareen N, Dhingra S. Stem cell therapy for cardiac regeneration: hits and misses. Can J Physiol Pharmacol 2015; 93:835-41. [DOI: 10.1139/cjpp-2014-0468] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cardiac injury and loss of cardiomyocytes is a causative as well as a resultant condition of cardiovascular disorders, which are the leading cause of death throughout the world. This loss of cardiomyocytes cannot be completely addressed through the currently available drugs being administered, which mainly function only in relieving the symptoms. There is a huge potential being investigated for regenerative and cell replacement therapies through recruiting stem cells of various origins namely embryonic, reprogramming/induction, and adult tissue. These sources are being actively studied for translation to clinical scenarios. In this review, we attempt to discuss some of these promising scenarios, including the clinical trials and the obstacles that need to be overcome, and hope to address the direction in which stem cell therapy is heading.
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Affiliation(s)
- Jagjit Padda
- Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, R 3028-2, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada
- Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, R 3028-2, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada
| | - Glen Lester Sequiera
- Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, R 3028-2, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada
- Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, R 3028-2, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada
| | - Niketa Sareen
- Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, R 3028-2, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada
- Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, R 3028-2, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada
| | - Sanjiv Dhingra
- Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, R 3028-2, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada
- Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, R 3028-2, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada
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22
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Qi H, Chen G, Huang Y, Si Z, Li J. Foxp3-modified bone marrow mesenchymal stem cells promotes liver allograft tolerance through the generation of regulatory T cells in rats. J Transl Med 2015; 13:274. [PMID: 26293578 PMCID: PMC4545923 DOI: 10.1186/s12967-015-0638-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 08/13/2015] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The transcription factor forkhead box P3 (Foxp3) is a master regulatory gene necessary for the development and function of CD4(+)CD25(+) regulatory T cells (Tregs). Mesenchymal stem cells (MSC) have recently emerged as promising candidates for cell-based immunosuppression/tolerance induction protocols. Thus, we hypothesized that MSC-based Foxp3 gene therapy would improve immunosuppressive capacity of MSC and induce donor-specific allograft tolerance in rat's liver allograft model. METHODS The present study utilized a lentivirus vector to overexpress the therapeutic gene Foxp3 on MSC. In vivo, Injections of 2 × 10(6) MSC, FUGW-MSC or Foxp3-MSC into the portal vein were carried out immediately after liver transplantation. RESULTS Successful gene transfer of Foxp3 in MSC was achieved by lentivirus carrying Foxp3 and Foxp3-MSC engraftment in liver allograft was confirmed by fluorescence microscopy. Foxp3-MSC treatment significantly inhibited the proliferation of allogeneic ACI CD4(+) T cells to splenocytes (SC) from the same donor strain or third-party BN rat compared with MSC. Foxp3-MSC suppressive effect on the proliferation of CD4(+) T cells is contact dependent and associated with Programmed death ligand 1(PD-L1) upregulation in MSC. Co-culture of CD4(+) T cells with Foxp3-MSC results in a shift towards a Tregs phenotype. More importantly, Foxp3-MSC monotherapy achieved donor-specific liver allograft tolerance and generated a state of CD4(+)CD25(+)Foxp3(+) Tregs-dependent tolerance. CONCLUSION Foxp3-engineered MSC therapy seems to be a promising and attractive cell therapy approach for inducing immunosuppression or transplant tolerance.
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Affiliation(s)
- Haizhi Qi
- Department of Organ Transplantation, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, Hunan, China.
| | - Guangshun Chen
- Department of Organ Transplantation, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, Hunan, China.
| | - Yaxun Huang
- Department of Organ Transplantation, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, Hunan, China.
| | - Zhongzhou Si
- Department of Organ Transplantation, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, Hunan, China.
| | - Jiequn Li
- Department of Organ Transplantation, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, Hunan, China.
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Human Wharton's jelly mesenchymal stem cell secretome display antiproliferative effect on leukemia cell line and produce additive cytotoxic effect in combination with doxorubicin. Tissue Cell 2015; 47:229-34. [DOI: 10.1016/j.tice.2015.01.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Revised: 01/22/2015] [Accepted: 01/22/2015] [Indexed: 12/22/2022]
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Tsuji W, Schnider JT, McLaughlin MM, Schweizer R, Zhang W, Solari MG, Rubin JP, Marra KG, Plock JA, Gorantla VS. Effects of immunosuppressive drugs on viability and susceptibility of adipose- and bone marrow-derived mesenchymal stem cells. Front Immunol 2015; 6:131. [PMID: 25932028 PMCID: PMC4399413 DOI: 10.3389/fimmu.2015.00131] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Accepted: 03/10/2015] [Indexed: 01/22/2023] Open
Abstract
The immunomodulatory potential of cell therapies using adipose-derived stem cells (ASCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs) has been studied in vascularized composite allotransplantation (VCA). Most cell therapy-based experimental and clinical protocols integrate some degree of recipient conditioning/induction with antibodies or other immunosuppressive agents. We investigated the susceptibility of ASCs and BM-MSCs to anti-lymphocyte serum (ALS) and tacrolimus. Rat ASCs and BM-MSCs were exposed to varying concentrations of tacrolimus and ALS in vitro. Serum from ALS-treated animals was added to cell cultures. Viability, susceptibility, and cytotoxicity parameters were evaluated. ALS inhibited ASC and BM-MSC viability and susceptibility in vitro in a dose-dependent manner. ASCs were more susceptible to both ALS and tacrolimus than BM-MSCs. Trypsinized and adherent ASCs were significantly smaller than BM-MSCs. This is the first report on the viability and susceptibility characteristics of BM-MSCs or ASCs to collateral effects of ALS and tacrolimus. These in vitro insights may impact choice of cell type as well as concomitant conditioning agents and the logistical coordination of the timing, dosing, and frequency of drug or cell therapy in solid organ transplantation or VCA protocols.
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Affiliation(s)
- Wakako Tsuji
- Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Surgery, Shiga Medical Center for Adults , Moriyama , Japan
| | - Jonas T Schnider
- Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, PA , USA
| | - Meghan M McLaughlin
- Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, PA , USA
| | - Riccardo Schweizer
- Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Plastic Surgery and Hand Surgery, University Hospital Zurich , Zurich , Switzerland
| | - Wensheng Zhang
- Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, PA , USA
| | - Mario G Solari
- Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, PA , USA
| | - J Peter Rubin
- Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Bioengineering, University of Pittsburgh , Pittsburgh, PA , USA
| | - Kacey G Marra
- Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Bioengineering, University of Pittsburgh , Pittsburgh, PA , USA
| | - Jan A Plock
- Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Plastic Surgery and Hand Surgery, University Hospital Zurich , Zurich , Switzerland
| | - Vijay S Gorantla
- Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA
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25
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Overcoming immunological barriers in regenerative medicine. Nat Biotechnol 2015; 32:786-94. [PMID: 25093888 DOI: 10.1038/nbt.2960] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 06/14/2014] [Indexed: 02/06/2023]
Abstract
Regenerative therapies that use allogeneic cells are likely to encounter immunological barriers similar to those that occur with transplantation of solid organs and allogeneic hematopoietic stem cells (HSCs). Decades of experience in clinical transplantation hold valuable lessons for regenerative medicine, offering approaches for developing tolerance-induction treatments relevant to cell therapies. Outside the field of solid-organ and allogeneic HSC transplantation, new strategies are emerging for controlling the immune response, such as methods based on biomaterials or mimicry of antigen-specific peripheral tolerance. Novel biomaterials can alter the behavior of cells in tissue-engineered constructs and can blunt host immune responses to cells and biomaterial scaffolds. Approaches to suppress autoreactive immune cells may also be useful in regenerative medicine. The most innovative solutions will be developed through closer collaboration among stem cell biologists, transplantation immunologists and materials scientists.
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26
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Sivanathan KN, Gronthos S, Rojas-Canales D, Thierry B, Coates PT. Interferon-gamma modification of mesenchymal stem cells: implications of autologous and allogeneic mesenchymal stem cell therapy in allotransplantation. Stem Cell Rev Rep 2014; 10:351-75. [PMID: 24510581 DOI: 10.1007/s12015-014-9495-2] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Bone marrow-derived mesenchymal stem cells (MSC) have unique immunomodulatory and reparative properties beneficial for allotransplantation cellular therapy. The clinical administration of autologous or allogeneic MSC with immunosuppressive drugs is able to prevent and treat allograft rejection in kidney transplant recipients, thus supporting the immunomodulatory role of MSC. Interferon-gamma (IFN-γ) is known to enhance the immunosuppressive properties of MSC. IFN-γ preactivated MSC (MSC-γ) directly or indirectly modulates T cell responses by enhancing or inducing MSC inhibitory factors. These factors are known to downregulate T cell activation, enhance T cell negative signalling, alter T cells from a proinflammatory to an anti-inflammatory phenotype, interact with antigen-presenting cells and increase or induce regulatory cells. Highly immunosuppressive MSC-γ with increased migratory and reparative capacities may aid tissue repair, prolong allograft survival and induce allotransplant tolerance in experimental models. Nevertheless, there are contradictory in vivo observations related to allogeneic MSC-γ therapy. Many studies report that allogeneic MSC are immunogenic due to their inherent expression of major histocompatibility (MHC) molecules. Enhanced expression of MHC in allogeneic MSC-γ may increase their immunogenicity and this can negatively impact allograft survival. Therefore, strategies to reduce MSC-γ immunogenicity would facilitate "off-the-shelf" MSC therapy to efficiently inhibit alloimmune rejection and promote tissue repair in allotransplantation. In this review, we examine the potential benefits of MSC therapy in the context of allotransplantation. We also discuss the use of autologous and allogeneic MSC and the issues associated with their immunogenicity in vivo, with particular focus on the use of enhanced MSC-γ cellular therapy.
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Affiliation(s)
- Kisha Nandini Sivanathan
- School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, 5005, South Australia, Australia,
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Obermajer N, Popp FC, Soeder Y, Haarer J, Geissler EK, Schlitt HJ, Dahlke MH. Conversion of Th17 into IL-17Aneg Regulatory T Cells: A Novel Mechanism in Prolonged Allograft Survival Promoted by Mesenchymal Stem Cell–Supported Minimized Immunosuppressive Therapy. THE JOURNAL OF IMMUNOLOGY 2014; 193:4988-99. [DOI: 10.4049/jimmunol.1401776] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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28
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Li F, Zhao SZ. Mesenchymal stem cells: Potential role in corneal wound repair and transplantation. World J Stem Cells 2014; 6:296-304. [PMID: 25126379 PMCID: PMC4131271 DOI: 10.4252/wjsc.v6.i3.296] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/06/2014] [Accepted: 04/11/2014] [Indexed: 02/06/2023] Open
Abstract
Corneal diseases are a major cause of blindness in the world. Although great progress has been achieved in the treatment of corneal diseases, wound healing after severe corneal damage and immunosuppressive therapy after corneal transplantation remain problematic. Mesenchymal stem cells (MSCs) derived from bone marrow or other adult tissues can differentiate into various types of mesenchymal lineages, such as osteocytes, adipocytes, and chondrocytes, both in vivo and in vitro. These cells can further differentiate into specific cell types under specific conditions. MSCs migrate to injury sites and promote wound healing by secreting anti-inflammatory and growth factors. In addition, MSCs interact with innate and acquired immune cells and modulate the immune response through their powerful paracrine function. Over the last decade, MSCs have drawn considerable attention because of their beneficial properties and promising therapeutic prospective. Furthermore, MSCs have been applied to various studies related to wound healing, autoimmune diseases, and organ transplantation. This review discusses the potential functions of MSCs in protecting corneal tissue and their possible mechanisms in corneal wound healing and corneal transplantation.
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Lett B, Sivanathan KN, Coates PT. Mesenchymal stem cells for kidney transplantation. World J Clin Urol 2014; 3:87-95. [DOI: 10.5410/wjcu.v3.i2.87] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 06/06/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
The long term consequence of immunosuppressive therapy in kidney transplantation has prompted investigation of alternative means to modify the immune response to the allograft. Cell based therapies are potentially attractive as they may provide a long lasting immunomodulatory effect, may repair tissues and reduce the necessity to take immunosuppressive drug therapy. Of the current cell therapies, mesenchymal stem cells have now been trialled in small numbers of human kidney transplantation with apparent safety and potential efficacy. Many issues however need to be resolved before these cells will become mainstays of transplant immunosuppression including ex vivo modification to enhance immunomodulatory properties, cell number, route and frequency of administration as well as cellular source of origin.
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Nemeth K. Mesenchymal stem cell therapy for immune-modulation: the donor, the recipient, and the drugs in-between. Exp Dermatol 2014; 23:625-8. [PMID: 24863432 DOI: 10.1111/exd.12459] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/22/2014] [Indexed: 02/06/2023]
Abstract
Adoptive transfer of cultured bone marrow stromal cells (mesenchymal stem cells also known as MSCs) is a promising new way to aid tissue regeneration and treat a wide variety of diseases where regulation of inflammatory responses is derailed. Although significant advances have been made in the field, pinpointing important mechanistic details about how MSCs function in vitro and in vivo, there are still many unanswered questions that need to be addressed before welcoming MSCs in the therapeutic arsenal of immune mediated diseases. In this viewpoint, we highlight and discuss a few factors that we believe are critical in terms of therapeutic success employing cultured MSCs. Selecting the right donor population, choosing the best culture conditions and picking the patient population that is most likely to give a favourable therapeutic response is just as important as considering interactions between MSCs and the combination of drugs in the recipient's body. Given the complexity of MSC-host interactions, it is also imperative to develop screening tools that account for as many variables as possible and predict precisely the in vivo response rates before MSCs enter the body. To achieve this, a multidisciplinary approach is required with comprehensive knowledge of basic MSC biology, immunology, pharmacology and good clinical practice.
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Affiliation(s)
- Krisztian Nemeth
- Department of Dermatology, Dermatooncology, and Venerology, Semmelweis University, Budapest, Hungary
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31
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Rationale and prospects of mesenchymal stem cell therapy for liver transplantation. Curr Opin Organ Transplant 2014; 19:60-4. [DOI: 10.1097/mot.0000000000000031] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Abstract
Immunomodulatory cell therapy as a complement to standard pharmacotherapy represents a novel approach to solid organ allograft acceptance. This methodology may allow for a reduced dose of immunosuppressive drug to be administered and thus attenuate the severe side effects associated with long-term immunosuppression such as drug-related impairment of renal function, increased risk from opportunistic infections and malignancies. Mesenchymal stem cells (MSCs) have been shown to possess both immune modulatory and regenerative properties in vitro and in preclinical models. Encouraging results have been reported from studies examining the safety and efficacy of MSCs as a treatment for acute graft-versus-host disease. MSCs represent a promising candidate cell therapy to supplement immunosuppression in recipients of solid organs, and initial reports on the clinical use of MSCs in kidney transplantation have been recently published (Tan et al. in J Am Med Assoc 307:1169-1177, 2012; Reinders et al. in Stem Cells Transl Med 2:107-111, 2013; Perico et al. in Transpl Int 26:867-878, 2013; Perico et al. in Clin J Am Soc Nephrol 6:412-422, 2011). An area of even greater interest might be the application of MSCs in clinical liver transplantation as graft survival is closely associated with overall patient survival. Here, we present preclinical findings and discuss their possible impact on clinical liver transplantation. Then we discuss clinical studies designed to investigate how MSCs may be distributed and act in solid organ transplantation.
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Reinders ME, Hoogduijn MJ. NK Cells and MSCs: Possible Implications for MSC Therapy in Renal Transplantation. ACTA ACUST UNITED AC 2014; 4:1000166. [PMID: 24900946 PMCID: PMC4040539 DOI: 10.4172/2157-7633.1000166] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Marlies Ej Reinders
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Martin J Hoogduijn
- Transplantation and Nephrology, Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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Dorronsoro A, Ferrin I, Salcedo JM, Jakobsson E, Fernández-Rueda J, Lang V, Sepulveda P, Fechter K, Pennington D, Trigueros C. Human mesenchymal stromal cells modulate T-cell responses through TNF-α-mediated activation of NF-κB. Eur J Immunol 2013; 44:480-8. [PMID: 24307058 DOI: 10.1002/eji.201343668] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 10/02/2013] [Accepted: 10/31/2013] [Indexed: 12/17/2022]
Abstract
Although mesenchymal stromal cells (MSCs) possess the capacity to modulate immune responses, little is known about the mechanisms that underpin these processes. In this study, we show that immunosupression is mediated by activation of nuclear factor kappa B (NF-κB) in human MSCs. This pathway is activated by TNF-α that is generated following TCR stimulation of T cells. Inhibition of NF-κB through silencing of IκB kinase β or the TNF-α receptor abolishes the immunosuppressive capacity of MSCs. Our data also indicate that MSC-associated NF-κB activation primarily leads to inhibition of T-cell proliferation with little effect on expression of the activation markers CD69 and CD25. Thus, our data support the hypothesis that the TNF-α/NF-κB signalling pathway is required for the initial priming of immunosuppressive function in human MSCs. Interestingly, drugs that interfere with NF-κB activation significantly antagonise the immunoregulatory effect of MSCs, which could have important implications for immunosuppression regimens in the clinic.
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Affiliation(s)
- Akaitz Dorronsoro
- Mesenchymal and Hematopoietic Stem Cell Laboratory, Foundation for Stem Cell Research, Fundación Inbiomed, San Sebastián, Spain
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Plock JA, Schnider JT, Solari MG, Zheng XX, Gorantla VS. Perspectives on the use of mesenchymal stem cells in vascularized composite allotransplantation. Front Immunol 2013; 4:175. [PMID: 23888159 PMCID: PMC3719134 DOI: 10.3389/fimmu.2013.00175] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 06/18/2013] [Indexed: 12/13/2022] Open
Abstract
Reconstructive transplantation has emerged as clinical reality over the past decade. Long-term graft acceptance has been feasible in extremity and facial vascularized composite allotransplantation (VCA) under standard immunosuppression. Minimizing overall burden of lifelong immunosuppression is key to wider application of these non-life saving grafts. Allograft tolerance is the holy grail of many cell-based immunomodulatory strategies. Recent protocols using mesenchymal stem cells from bone marrow and adipose tissue offer promise and potential in VCA. This article provides an overview of the experimental basis, the scientific background and clinical applications of stem cell-based therapies in the field of reconstructive allotransplantation.
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Affiliation(s)
- Jan A Plock
- Department of Plastic Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA , USA ; Division of Plastic and Hand Surgery, University Hospital Zurich , Zurich , Switzerland
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Eggenhofer E, Popp FC, Mendicino M, Silber P, Van't Hof W, Renner P, Hoogduijn MJ, Pinxteren J, van Rooijen N, Geissler EK, Deans R, Schlitt HJ, Dahlke MH. Heart grafts tolerized through third-party multipotent adult progenitor cells can be retransplanted to secondary hosts with no immunosuppression. Stem Cells Transl Med 2013; 2:595-606. [PMID: 23836805 DOI: 10.5966/sctm.2012-0166] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Multipotent adult progenitor cells (MAPCs) are an adherent stem cell population that belongs to the mesenchymal-type progenitor cell family. Although MAPCs are emerging as candidate agents for immunomodulation after solid organ transplantation, their value requires further validation in a clinically relevant cell therapy model using an organ donor- and organ recipient-independent, third-party cell product. We report that stable allograft survival can be achieved following third-party MAPC infusion in a rat model of fully allogeneic, heterotopic heart transplantation. Furthermore, long-term accepted heart grafts recovered from MAPC-treated animals can be successfully retransplanted to naïve animals without additional immunosuppression. This prolongation of MAPC-mediated allograft acceptance depends upon a myeloid cell population since depletion of macrophages by clodronate abrogates the tolerogenic MAPC effect. We also show that MAPC-mediated allograft acceptance differs mechanistically from drug-induced tolerance regarding marker gene expression, T regulatory cell induction, retransplantability, and macrophage dependence. MAPC-based immunomodulation represents a promising pathway for clinical immunotherapy that has led us to initiate a phase I clinical trial for testing safety and feasibility of third-party MAPC therapy after liver transplantation.
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Affiliation(s)
- Elke Eggenhofer
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
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37
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Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol 2013; 91:32-9. [PMID: 23295415 PMCID: PMC3540326 DOI: 10.1038/icb.2012.64] [Citation(s) in RCA: 163] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Somatic, also termed adult, stem cells are highly attractive biomedical cell candidates because of their extensive replication potential and functional multilineage differentiation capacity. They can be used for drug and toxicity screenings in preclinical studies, as in vitro model to study differentiation or for regenerative medicine to aid in the repair of tissues or replace tissues that are lost upon disease, injury or ageing. Multipotent adult progenitor cells (MAPCs) and mesenchymal stem cells (MSCs) are two types of adult stem cells derived from bone marrow that are currently being used clinically for tissue regeneration and for their immunomodulatory and trophic effects. This review will give an overview of the phenotypic and functional differences between human MAPCs and MSCs, with a strong emphasis on their immunological characteristics. Finally, we will discuss the clinical studies in which MSCs and MAPCs are already used.
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38
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English K, Wood KJ. Mesenchymal stromal cells in transplantation rejection and tolerance. Cold Spring Harb Perspect Med 2013; 3:a015560. [PMID: 23637312 PMCID: PMC3633184 DOI: 10.1101/cshperspect.a015560] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stromal cells (MSCs) have recently emerged as promising candidates for cell-based immunotherapy in solid organ transplantation (SOT). In addition to immune modulation, MSCs possess proreparative properties and preclinical studies indicate that MSCs have the capacity to prolong graft survival and in some cases induce tolerance. Currently, the application of MSCs in SOT is being evaluated in phase I/II clinical trials. Whereas the mechanisms of action used by MSC immunomodulation have been somewhat elucidated in vitro, the data from preclinical transplant models have been unclear. Furthermore, the optimal timing, dose, and route of administration remain to be elucidated. Importantly, MSCs have the ability to sense their environment, which may influence their function. In this article, we discuss the impact of the local microenvironment on MSCs and the mechanisms of MSC immunomodulation in the setting of SOT.
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Affiliation(s)
- Karen English
- Cellular Immunology Group, Institute of Immunology, National University of Ireland Maynooth, County Kildare, Ireland.
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39
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The role of mesenchymal stromal cells in chronic transplant rejection after solid organ transplantation. Curr Opin Organ Transplant 2013; 18:44-50. [DOI: 10.1097/mot.0b013e32835c2939] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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40
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Molecular characteristics of bone marrow mesenchymal stem cells, source of regenerative medicine. Int J Cardiol 2013; 163:125-31. [DOI: 10.1016/j.ijcard.2011.11.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Revised: 11/03/2011] [Accepted: 11/04/2011] [Indexed: 12/22/2022]
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Abstract
Mesenchymal stem cells (MSCs) are multipotent adult stem cells which have self-renewal capacity and differentiation potential into several mesenchymal lineages including bones, cartilages, adipose tissues and tendons. MSCs may repair tissue injuries and prevent immune cell activation and proliferation. Immunomodulation and secretion of growth factors by MSCs have led to realizing the true potential of MSC-based cell therapy. The use of MSCs as immunomodulators has been explored in cell/organ transplant, tissue repair, autoimmune diseases, and prevention of graft vs host disease (GVHD). This review focuses on the clinical applications of MSC-based cell therapy, with particular emphasis on islet transplantation for treating type I diabetes.
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Affiliation(s)
- Vaibhav Mundra
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38103, United States
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42
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Macedo C, Turquist H, Metes D, Thomson AW. Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation. Transplant Res 2012; 1:16. [PMID: 23369601 PMCID: PMC3560974 DOI: 10.1186/2047-1440-1-16] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Accepted: 09/04/2012] [Indexed: 12/14/2022] Open
Abstract
In efforts to minimize the chronic administration of immunosuppression (IS) drugs in transplantation and autoimmune disease, various cell-based tolerogenic therapies, including the use of regulatory or tolerogenic dendritic cells (tolDC) have been developed. These DC-based therapies aim to harness the inherent immunoregulatory potential of these professional antigen-presenting cells. In this short review, we describe both the demonstrated tolerogenic properties, and current limitations of rapamycin-conditioned DC (RAPA-DC). RAPA-DC are generated through inhibition of the integrative kinase mammalian target of rapamycin (mTOR) by the immunosuppressive macrolide rapamycin during propagation of monocyte-derived DC. Consistent with the characteristics of tolDC, murine RAPA-DC display resistance to phenotypic maturation induced by pro-inflammatory stimuli; exhibit the ability to migrate to secondary lymphoid tissue (important for 'cross-presentation' of antigen to T cells), and enrich for naturally-occurring CD4+ regulatory T cells. In rodent models, delivery of recipient-derived RAPA-DC pulsed with donor antigen prior to organ transplantation can prolong allogeneic heart-graft survival indefinitely, especially when combined with a short course of IS. These encouraging data support ongoing efforts to develop RAPA-DC for clinical testing. When compared to murine RAPA-DC however, human RAPA-DC have proven only partially resistant to maturation triggered by pro-inflammatory cytokines, and display heterogeneity in their impact on effector T-cell expansion and function. In total, the evidence suggests the need for more in-depth studies to better understand the mechanisms by which mTOR controls human DC function. These studies may facilitate the development of RAPA-DC therapy alone or together with agents that preserve/enhance their tolerogenic properties as clinical immunoregulatory vectors.
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Affiliation(s)
- Camila Macedo
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA
| | - Hēth Turquist
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA
- Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA
| | - Diana Metes
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA
- Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA
| | - Angus W Thomson
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA
- Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA
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Pourrajab F, Forouzannia SK, Tabatabaee SA. WITHDRAWN: Molecular Characteristics of Bone Marrow Mesenchymal Stem Cells: An Appealing Source for Regenerative Medicine. Heart Lung Circ 2012:S1443-9506(12)00258-2. [PMID: 22939816 DOI: 10.1016/j.hlc.2012.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Revised: 10/08/2011] [Accepted: 04/26/2012] [Indexed: 11/18/2022]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.hlc.2012.04.021. The duplicate article has therefore been withdrawn.
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Affiliation(s)
- Fatemeh Pourrajab
- Yazd Cardiovascular Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Department of Clinical Biochemistry, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Leijs MJC, van Buul GM, Lubberts E, Bos PK, Verhaar JAN, Hoogduijn MJ, van Osch GJVM. Effect of Arthritic Synovial Fluids on the Expression of Immunomodulatory Factors by Mesenchymal Stem Cells: An Explorative in vitro Study. Front Immunol 2012; 3:231. [PMID: 22876244 PMCID: PMC3410447 DOI: 10.3389/fimmu.2012.00231] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 07/14/2012] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND In diseased joints, the catabolic environment results in progressive joint damage. Mesenchymal stem cells (MSCs) can have immunomodulatory effects by secreting anti-inflammatory factors. To exert these effects, MSCs need to be triggered by pro-inflammatory cytokines. To explore the potential of MSCs as a treatment for diseased joints, we studied the effect of synovial fluid (SF) from donors with different joint diseases and donors without joint pathology on the immunomodulatory capacities of human MSCs in vitro. We hypothesized that SF of diseased joints influences the immunomodulatory effects of MSCs. MATERIALS AND METHODS MSCs were cultured in medium with SF of six osteoarthritis (OA) or six rheumatoid arthritis (RA) donors and three donors without joint pathology were used as control. Gene expressions of IL-6, HGF, TNFa, TGFb1, and indoleamine 2,3-dioxygenase (IDO) were analyzed. l-kynurenine concentration in conditioned medium (CM) by MSCs with SF was determined as a measure of IDO activity by MSCs. Furthermore, the effect of CM with SF on proliferation of activated lymphocytes was analyzed. RESULTS Addition of SF significantly up-regulated the mRNA expression of IL-6 and IDO in MSCs. SF(OA) induced significantly higher expression of IDO than SF(control), although no difference in IDO activity of the MSCs could be shown with a l-kynurenine assay. Medium conditioned by MSCs with SF(OA or RA) suppressed activated lymphocyte proliferation in vitro more than medium conditioned by MSCs without SF or with SF(control). DISCUSSION SF can influence the expression of genes involved in immunomodulation by MSCs and the effect on lymphocyte proliferation. We found indications for disease-specific differences between SFs but the variation between donors, even within one disease group was high. These data warrant further research to examine the potential application of MSC therapy in arthritic joints.
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Affiliation(s)
- Maarten J C Leijs
- Department of Orthopaedics, Erasmus MC University Medical Center Rotterdam, The Netherlands
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45
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Sullivan C, Murphy JM, Griffin MD, Porter RM, Evans CH, O'Flatharta C, Shaw G, Barry F. Genetic mismatch affects the immunosuppressive properties of mesenchymal stem cells in vitro and their ability to influence the course of collagen-induced arthritis. Arthritis Res Ther 2012; 14:R167. [PMID: 22812502 PMCID: PMC3580561 DOI: 10.1186/ar3916] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Accepted: 07/19/2012] [Indexed: 01/01/2023] Open
Abstract
Introduction The immunological and homing properties of mesenchymal stem cells (MSCs) provide a potentially attractive treatment for arthritis. The objective of this study was to determine effects of genetic disparity on the immunosuppressive potential of MSCs in vitro and in vivo within collagen induced arthritis (CIA). Methods The ability of DBA/1, FVB and BALB/c MSC preparations to impact the cytokine release profile of CD3/CD28 stimulated DBA/1 T cells was assessed in vitro. The effect of systemically delivered MSCs on the progression of CIA and cytokine production was assessed in vivo. Results All MSC preparations suppressed the release of TNFα and augmented the secretion of IL-4 and IL-10 by stimulated DBA/1 T-cells. However, assessment of the ratio of IFNγ to IL-4 production indicated that the more genetically distant BALB/c MSCs had significantly less immunosuppressive capacity. Systemic delivery of BALB/c MSC resulted in an exacerbation of CIA disease score in vivo and a higher erosive disease burden. This was not seen after treatment with syngeneic or partially mismatched MSCs. An increase in serum levels of IL-1β was observed up to 20 days post treatment with allogeneic MSCs. An initial elevation of IL-17 in these treatment groups persisted in those treated with fully mismatched BALB/c MSCs. Over the course of the study, there was a significant suppression of serum IL-17 levels in groups treated with syngeneic MSCs. Conclusions These data demonstrate a significant difference in the immunosuppressive properties of syngeneic and allogeneic MSCs in vitro and in vivo, which needs to be appreciated when developing MSC based therapies for inflammatory arthritis.
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Seifert M, Stolk M, Polenz D, Volk HD. Detrimental effects of rat mesenchymal stromal cell pre-treatment in a model of acute kidney rejection. Front Immunol 2012; 3:202. [PMID: 22826709 PMCID: PMC3398550 DOI: 10.3389/fimmu.2012.00202] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 06/28/2012] [Indexed: 12/21/2022] Open
Abstract
Mesenchymal stromal cells (MSC) have shown immunomodulatory and tissue repair potential including partial tolerance induction by pre-treatment of donor-specific cells in a rat heart transplantation model. Very recently, we could show that autologous MSC attenuated ischemia reperfusion injury in a highly mismatched donor–recipient rat kidney transplant model. Therefore, we investigated donor-specific MSC pre-treatment in this rat kidney transplantation model to study whether graft function could be improved, or if tolerance could be induced. Donor- and recipient-type MSC or phosphate buffered saline (PBS) as a control was injected i.v. 4 days before kidney transplantation. Mycophenolate mofetil immunosuppression (20mg/kg body weight) was applied for 7 days. Kidney grafts and spleens were harvested between days 8 and 10 and analyzed by quantitative RT-PCR and immunohistology. In addition, creatinine levels in the blood were measured and serum was screened for the presence of donor-specific antibodies. Surprisingly, application of both donor- and recipient-specific MSC resulted in enhanced humoral immune responses verified by intragraft B cell infiltration and complement factor C4d deposits. Moreover, signs of inflammation and rejection were generally enhanced in both MSC-treated groups relative to PBS control group. Additionally, pre-treatment with donor-specific MSC significantly enhanced the level of donor-specific antibody formation when compared with PBS- or recipient MSC-treated groups. Pre-treatment with both MSC types resulted in a higher degree of kidney cortex tissue damage and elevated creatinine levels at the time point of rejection. Thus, MSC pre-sensitization in this model impairs the allograft outcome. Our data from this pre-clinical kidney transplantation model indicate that pre-operative MSC administration may not be optimal in kidney transplantation and caution must be exerted before moving forward with clinical studies in order to avoid adverse effects.
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Affiliation(s)
- Martina Seifert
- Berlin-Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin Berlin , Berlin, Germany
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47
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Baiguera S, Jungebluth P, Mazzanti B, Macchiarini P. Mesenchymal stromal cells for tissue-engineered tissue and organ replacements. Transpl Int 2012; 25:369-82. [PMID: 22248229 DOI: 10.1111/j.1432-2277.2011.01426.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Mesenchymal stromal cells (MSCs), a rare heterogeneous subset of pluripotent stromal cells that can be easily isolated from different adult tissues, in vitro expanded and differentiated into multiple lineages, are immune privileged and, more important, display immunomodulatory capacities. Because of this, they are the preferred cell source in tissue-engineered replacements, not only in autogeneic conditions, where they do not evoke any immune response, but especially in the setting of allogeneic organ and tissue replacements. However, more preclinical and clinical studies are requested to completely understand MSC's immune biology and possible clinical applications. We herein review the immunogenicity and immunomodulatory properties of MSCs, their possible mechanisms and potential clinical use for tissue-engineered organ and tissue replacement.
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Affiliation(s)
- Silvia Baiguera
- BIOAIRlab, European Center of Thoracic Research (CERT), University Hospital Careggi, Florence, Italy
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49
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Hara Y, Stolk M, Ringe J, Dehne T, Ladhoff J, Kotsch K, Reutzel-Selke A, Reinke P, Volk HD, Seifert M. In vivo effect of bone marrow-derived mesenchymal stem cells in a rat kidney transplantation model with prolonged cold ischemia. Transpl Int 2011; 24:1112-23. [PMID: 21880071 DOI: 10.1111/j.1432-2277.2011.01328.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Brain death and prolonged cold ischemia are major contributors to the poorer long-term outcome of transplants from deceased donor kidney transplants, with an even higher impact if expanded criteria donors ('marginal organs') are used. Targeting ischemia-reperfusion injury-related intragraft inflammation is an attractive concept to improve the outcome of those grafts. As mesenchymal stem cells (MSCs) express both immunomodulatory and tissue repair properties, we evaluated their therapeutic efficacy in a rat kidney transplant model of prolonged cold ischemia. The in vitro immunomodulatory capacity of bone marrow-derived rat MSCs was tested in co-cultures with rat lymph node cells. For in vivo studies, Dark Agouti rat kidneys were cold preserved and transplanted into Lewis rats. Syngeneic Lewis MSCs were administered intravenously. Transplants were harvested on day 3, and inflammation was examined by quantitative RT-PCR and histology. Similarly to MSCs from other species, rat MSCs in vitro also showed a dose-dependent immunomodulatory capacity. Most importantly, in vivo administration of MSCs reduced the intragraft gene expression of different pro-inflammatory cytokines, chemokines, and intercellular adhesion molecule-1. In addition, fewer antigen-presenting cells were recruited into the renal allograft. In conclusion, rat MSCs ameliorate inflammation induced by prolonged cold ischemia in kidney transplantation.
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Affiliation(s)
- Yoshiaki Hara
- Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
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Popp FC, Fillenberg B, Eggenhofer E, Renner P, Dillmann J, Benseler V, Schnitzbauer AA, Hutchinson J, Deans R, Ladenheim D, Graveen CA, Zeman F, Koller M, Hoogduijn MJ, Geissler EK, Schlitt HJ, Dahlke MH. Safety and feasibility of third-party multipotent adult progenitor cells for immunomodulation therapy after liver transplantation--a phase I study (MISOT-I). J Transl Med 2011; 9:124. [PMID: 21798013 PMCID: PMC3166276 DOI: 10.1186/1479-5876-9-124] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Accepted: 07/28/2011] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Liver transplantation is the definitive treatment for many end-stage liver diseases. However, the life-long immunosuppression needed to prevent graft rejection causes clinically significant side effects. Cellular immunomodulatory therapies may allow the dose of immunosuppressive drugs to be reduced. In the current protocol, we propose to complement immunosuppressive pharmacotherapy with third-party multipotent adult progenitor cells (MAPCs), a culture-selected population of adult adherent stem cells derived from bone marrow that has been shown to display potent immunomodulatory and regenerative properties. In animal models, MAPCs reduce the need for pharmacological immunosuppression after experimental solid organ transplantation and regenerate damaged organs. METHODS Patients enrolled in this phase I, single-arm, single-center safety and feasibility study (n = 3-24) will receive 2 doses of third-party MAPCs after liver transplantation, on days 1 and 3, in addition to a calcineurin-inhibitor-free "bottom-up" immunosuppressive regimen with basiliximab, mycophenolic acid, and steroids. The study objective is to evaluate the safety and clinical feasibility of MAPC administration in this patient cohort. The primary endpoint of the study is safety, assessed by standardized dose-limiting toxicity events. One secondary endpoint is the time until first biopsy-proven acute rejection, in order to collect first evidence of efficacy. Dose escalation (150, 300, 450, and 600 million MAPCs) will be done according to a 3 + 3 classical escalation design (4 groups of 3-6 patients each). DISCUSSION If MAPCs are safe for patients undergoing liver transplantation in this study, a phase II/III trial will be conducted to assess their clinical efficacy.
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Affiliation(s)
- Felix C Popp
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
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