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Ma L, Fink J, Yao K, McDonald-Hyman C, Dougherty P, Koehn B, Blazar BR. Immunoregulatory iPSC-derived non-lymphoid progeny in autoimmunity and GVHD alloimmunity. Stem Cells 2025; 43:sxaf011. [PMID: 40103180 DOI: 10.1093/stmcls/sxaf011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/19/2025] [Indexed: 03/20/2025]
Abstract
Non-lymphoid immunoregulatory cells, including mesenchymal stem cells (MSCs), myeloid-derived suppressor cells (MDSCs), regulatory macrophages (Mregs), and tolerogenic dendritic cells (Tol-DCs), play critical roles in maintaining immune homeostasis. However, their therapeutic application in autoimmune diseases and graft-versus-host disease (GVHD) has received comparatively less attention. Induced pluripotent stem cells (iPSCs) offer a promising platform for cell engineering, enabling superior quality control, scalable production, and large-scale in vitro expansion of iPSC-derived non-lymphoid immunoregulatory cells. These advances pave the way for their broader application in autoimmune disease and GVHD therapy. Recent innovations in iPSC differentiation protocols have facilitated the generation of these cell types with functional characteristics akin to their primary counterparts. This review explores the unique features and generation processes of iPSC-derived non-lymphoid immunoregulatory cells, their therapeutic potential in GVHD and autoimmune disease, and their progress toward clinical translation. It emphasizes the phenotypic and functional diversity within each cell type and their distinct effects on disease modulation. Despite these advancements, challenges persist in optimizing differentiation efficiency, ensuring functional stability, and bridging the gap to clinical application. By synthesizing current methodologies, preclinical findings, and translational efforts, this review underscores the transformative potential of iPSC-derived non-lymphoid immunoregulatory cells in advancing cell-based therapies for alloimmune and autoimmune diseases.
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Affiliation(s)
- Lie Ma
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Jordan Fink
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Ke Yao
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Cameron McDonald-Hyman
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, United States
| | - Phillip Dougherty
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Brent Koehn
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
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Ho QY, Hester J, Issa F. Regulatory cell therapy for kidney transplantation and autoimmune kidney diseases. Pediatr Nephrol 2025; 40:39-52. [PMID: 39278988 PMCID: PMC11584488 DOI: 10.1007/s00467-024-06514-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/13/2024] [Accepted: 08/18/2024] [Indexed: 09/18/2024]
Abstract
Regulatory cell therapies, including regulatory T cells and mesenchymal stromal cells, have shown promise in early clinical trials for reducing immunosuppression burden in transplantation. While regulatory cell therapies may also offer potential for treating autoimmune kidney diseases, data remains sparse, limited mainly to preclinical studies. This review synthesises current literature on the application of regulatory cell therapies in these fields, highlighting the safety and efficacy shown in existing clinical trials. We discuss the need for further clinical validation, optimisation of clinical and immune monitoring protocols, and the challenges of manufacturing and quality control under Good Manufacturing Practice conditions, particularly for investigator-led trials. Additionally, we explore the potential for expanding clinical indications and the unique challenges posed in paediatric applications. Future directions include scaling up production, refining protocols to ensure consistent quality across manufacturing sites, and extending applications to other immune-mediated diseases.
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Affiliation(s)
- Quan Yao Ho
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, Oxfordshire, UK
- Department of Renal Medicine, Singapore General Hospital, Singapore, Singapore
| | - Joanna Hester
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, Oxfordshire, UK
| | - Fadi Issa
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, Oxfordshire, UK.
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Levitte S, Nilkant R, Jensen AR, Zhang KY. Unlocking the promise of mesenchymal stem cells and extracorporeal photopheresis to address rejection and graft failure in intestinal transplant recipients. Hum Immunol 2024; 85:111160. [PMID: 39471538 DOI: 10.1016/j.humimm.2024.111160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/03/2024] [Accepted: 10/13/2024] [Indexed: 11/01/2024]
Abstract
INTRODUCTION In patients with irreversible intestinal failure, intestinal transplant has become a standard treatment option. Graft failure secondary to acute or chronic cellular rejection continues to be a significant challenge following transplant. Even with optimal immune suppression, some patients continue to struggle with refractory rejection. Both extracorporeal photopheresis (ECP) and extracellular vesicles derived from mesenchymal stem cells (EVs) have been used to treat refractory rejection following intestinal transplantation, although their use remains limited and consistent treatment protocols are lacking. METHODS Intestinal transplant recipients who received ECP only or ECP and EVs as rescue therapy for acute cellular rejection or chronic inflammation between 2016 and 2022 were included in this single-center retrospective analysis. Baseline demographics, pre- and post-treatment histopathology, endoscopic and biochemical findings, and long-term transplant outcomes were analyzed. RESULTS Three patients (two pediatric and one adult) with acute steroid- and biologic-refractory rejection were treated with ECP and/or EVs, as was one patient (pediatric) with chronic graft rejection and inflammation. Patients received twice weekly ECP for 4 weeks and once weekly thereafter. EVs were administered in three doses each separated by 72 h. Immunosuppression at the time of treatment initiation included high-dose tacrolimus and sirolimus. Histologic resolution of rejection was achieved in all patients over 12-16 weeks. Steroids were weaned to low-dose or withdrawn in every patient within 4 weeks of ECP/EV treatment. C-reactive protein decreased from an average of 14.75 to 1.6 mg/dL post-treatment and fecal calprotectin decreased from average 800 mg/g to 31 mg/g. Donor-induced cytotoxic T cell populations were quantified for two of the patients with acute rejection, and in both cases decreased dramatically following treatment. There were no complications associated with either treatment. CONCLUSION Both ECP and EVs present novel opportunities to address graft rejection and inflammation in bowel transplant recipients. More work will be needed to define the optimal therapeutic parameters for each treatment modality.
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Affiliation(s)
- Steven Levitte
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA
| | - Riya Nilkant
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
| | - Amanda R Jensen
- Department of Transplantation Surgery, Stanford University, Palo Alto, CA, USA
| | - Ke-You Zhang
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA.
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Fodor Duric L, Basic Jukic N, Vujicic B. Comparison of Autologous and Allogeneic Adipose-Derived Stem Cells in Kidney Transplantation: Immunological Considerations and Therapeutic Efficacy. J Clin Med 2024; 13:5763. [PMID: 39407823 PMCID: PMC11476955 DOI: 10.3390/jcm13195763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/18/2024] [Accepted: 09/22/2024] [Indexed: 10/20/2024] Open
Abstract
Regenerative medicine shows significant potential in treating kidney diseases through the application of various types of stem and progenitor cells, including mesenchymal stem cells (MSCs), renal stem/progenitor cells, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). Stem cells possess the unique ability to repair injured organs and improve impaired functions, making them a key element in the research of therapies for kidney tissue repair and organ regeneration. In kidney transplantation, reperfusion injury can cause tissue destruction, leading to an initially low glomerular filtration rate and long-term impact on function by creating irreversible interstitial fibrosis. MSCs have proven useful in repairing early tissue injury in animal models of kidney, lung, heart, and intestine transplantation. The use of stem cell therapies in solid organ transplantation raises the question of whether autologous or allogeneic cells should be preferred. Adipose-derived stem cells (ASCs), characterized by the lack of HLA Class II molecules and low expression of HLA Class I and co-stimulatory signals, are considered immune-privileged. However, the actual risk of graft rejection associated with allogeneic ASCs remains unclear. It has been demonstrated that donor-derived ASCs can promote the development of Treg cells in vitro, and some degree of tolerance induction has been observed in vivo. Nevertheless, a study comparing the efficacy of autologous and allogeneic ASCs in a rat model with a total MHC mismatch for kidney transplantation showed that donor-derived administration of ASCs did not improve the grafts' survival and was associated with increased mortality through an immunologically mediated mechanism. Given the lack of data, autologous ASCs appear to be a safer option in this research context. The aim of this review was to examine the differences between autologous and allogeneic ASCs in the context of their application in kidney transplantation therapies, considering potential immune reactions and therapeutic efficacy. Some have argued that ASCs harvested from end-stage renal disease (ESRD) patients may have lower regenerative potential due to the toxic effects of uremia, potentially limiting their use in transplantation settings. However, evidence suggests that the beneficial properties of ASCs are not affected by uremia or dialysis. Indeed, some investigators have demonstrated that ASCs harvested from chronic kidney disease (CKD) patients exhibit normal characteristics and function, maintaining consistent proliferative capacity and genetic stability over time, even after prolonged exposure to uremic serum Furthermore, no differences were observed in the response of ASCs to immune activation or their inhibitory effect on the proliferation of alloantigen-activated peripheral blood mononuclear cells between patients with normal or impaired renal function. This review presents the current achievements in stem cell research aimed at treating kidney diseases, highlighting significant progress and ongoing efforts in the development of stem cell-based therapies. Despite the encouraging results, further research is needed to overcome the current limitations and fully realize the potential of these innovative treatments. Advances in this field are crucial for developing effective therapies that can address the complex challenges associated with kidney damage and failure.
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Affiliation(s)
- Ljiljana Fodor Duric
- Medicol Polyclinic, School of Medicine, Croatian Catholic Unoversity, 10000 Zagreb, Croatia
| | - Nikolina Basic Jukic
- Department of Nephrology, Dialysis and Kidney Transplantation, Clinical Hospital Center Zagreb, Faculty of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Bozidar Vujicic
- Department of Nephrology, Dialysis and Kidney Transplantation, Clinical Hospital Center Rijeka, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia;
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Kaundal U, Rakha A. Differential effects of TLR3 and TLR4 activation on MSC-mediated immune regulation. Biochem Biophys Rep 2024; 39:101809. [PMID: 39228386 PMCID: PMC11369377 DOI: 10.1016/j.bbrep.2024.101809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 07/31/2024] [Accepted: 08/05/2024] [Indexed: 09/05/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) have evolved as an invaluable therapeutic cell type due to their broad therapeutic properties. Bone marrow-derived MSCs are currently being applied in numerous clinical trials, and the initial results have been encouraging. However, heterogeneous responsiveness amongst patients is also being experienced; therefore, the efficacy of MSCs in vivo is still debatable. Host microenvironment plays an essential role in determining the fate of MSCs in vivo. Recent studies have indicated the role of toll-like receptors (TLR) in modulating the biological properties of MSCs. TLRs are expressed by MSCs, and activation of TLR3 and TLR4 can alter the functionality of MSCs. While MSCs can suppress the effector and memory T cell function by promoting regulatory T cells, the effect of TLR activation on MSC-mediated immune cell induction is still not well understood. This study was performed to understand the TLR licensing of MSCs and its impact on MSC-mediated immunomodulation. We found that TLR3 mediated activation of MSCs (TLR3-MSCs) increased the expression of G-CSF & IL-10 while TLR4-mediated activation of MSCs led to an increase in CXCL-1, CXCL-10, and CXCL-12. To study the immunological aspect, an in vitro co-culture model was established-to imitate the brief in vivo interaction of MSCs and immune cells. We found that TLR3-MSCs led to increase in CD4 and CD8 naive T (TNAI) cells and vice versa for effector (TEFF) and memory T (TMEM) cells, while TLR4-MSCs did not show any effect. Moreover, only TLR3-MSCs led to a non-significant increase in the regulatory T cells (TREGS) and Double negative regulatory cells. No change in B cell profile was evident while TLR3-MSCs depicted an increasing trend in regulatory B cells which was not statistically significant. TLR3 MSCs also inhibited the T cell proliferation in our setup. Our data indicate that TLR3 priming may regulate the function of MSCs through immunomodulation. Understanding the role of TLRs and other microenvironmental factors causing subdued responses of MSCs in vivo would allow the uninhibited use of MSCs for many diseased conditions.
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Affiliation(s)
- Urvashi Kaundal
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India
- Scleroderma Genomics and Health Disparities Unit, NIAMS, NIH, Bethesda, USA
| | - Aruna Rakha
- Scleroderma Genomics and Health Disparities Unit, NIAMS, NIH, Bethesda, USA
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Mella A, Calvetti R, Barreca A, Congiu G, Biancone L. Kidney transplants from elderly donors: what we have learned 20 years after the Crystal City consensus criteria meeting. J Nephrol 2024; 37:1449-1461. [PMID: 38446386 PMCID: PMC11473582 DOI: 10.1007/s40620-024-01888-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 01/03/2024] [Indexed: 03/07/2024]
Abstract
Based on the current projection of the general population and the combined increase in end-stage kidney disease with age, the number of elderly donors and recipients is increasing, raising crucial questions about how to minimize the discard rate of organs from elderly donors and improve graft and patient outcomes. In 2002, extended criteria donors were the focus of a meeting in Crystal City (VA, USA), with a goal of maximizing the use of organs from deceased donors. Since then, extended criteria donors have progressively contributed to a large number of transplanted grafts worldwide, posing specific issues for allocation systems, recipient management, and therapeutic approaches. This review analyzes what we have learned in the last 20 years about extended criteria donor utilization, the promising innovations in immunosuppressive management, and the molecular pathways involved in the aging process, which constitute potential targets for novel therapies.
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Affiliation(s)
- Alberto Mella
- Renal Transplant Center" A. Vercellone," Nephrology, Dialysis, and Renal Transplant Division, "Città Della Salute e Della Scienza" Hospital, Department of Medical Sciences, University of Turin, Corso Bramante, 88, 10126, Turin, Italy
| | - Ruggero Calvetti
- Renal Transplant Center" A. Vercellone," Nephrology, Dialysis, and Renal Transplant Division, "Città Della Salute e Della Scienza" Hospital, Department of Medical Sciences, University of Turin, Corso Bramante, 88, 10126, Turin, Italy
| | - Antonella Barreca
- Division of Pathology, "Città Della Salute e Della Scienza" Hospital, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giovanni Congiu
- Renal Transplant Center" A. Vercellone," Nephrology, Dialysis, and Renal Transplant Division, "Città Della Salute e Della Scienza" Hospital, Department of Medical Sciences, University of Turin, Corso Bramante, 88, 10126, Turin, Italy
| | - Luigi Biancone
- Renal Transplant Center" A. Vercellone," Nephrology, Dialysis, and Renal Transplant Division, "Città Della Salute e Della Scienza" Hospital, Department of Medical Sciences, University of Turin, Corso Bramante, 88, 10126, Turin, Italy.
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Lindoso RS, Collino F, Kasai-Brunswick TH, Costa MR, Verdoorn KS, Einicker-Lamas M, Vieira-Beiral HJ, Wessely O, Vieyra A. Resident Stem Cells in Kidney Tissue. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:159-203. [DOI: 10.1016/b978-0-443-15289-4.00009-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Annamalai C, Kute V, Sheridan C, Halawa A. Hematopoietic cell-based and non-hematopoietic cell-based strategies for immune tolerance induction in living-donor renal transplantation: A systematic review. Transplant Rev (Orlando) 2023; 37:100792. [PMID: 37709652 DOI: 10.1016/j.trre.2023.100792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 04/24/2023] [Accepted: 08/17/2023] [Indexed: 09/16/2023]
Abstract
INTRODUCTION Despite its use to prevent acute rejection, lifelong immunosuppression can adversely impact long-term patient and graft outcomes. In theory, immunosuppression withdrawal is the ultimate goal of kidney transplantation, and is made possible by the induction of immunological tolerance. The purpose of this paper is to review the safety and efficacy of immune tolerance induction strategies in living-donor kidney transplantation, both chimerism-based and non-chimerism-based. The impact of these strategies on transplant outcomes, including acute rejection, allograft function and survival, cost, and immune monitoring, will also be discussed. MATERIALS AND METHODS Databases such as PubMed, Scopus, and Web of Science, as well as additional online resources such as EBSCO, were exhaustively searched. Adult living-donor kidney transplant recipients who developed chimerism-based tolerance after concurrent bone marrow or hematopoietic stem cell transplantation or those who received non-chimerism-based, non-hematopoietic cell therapy using mesenchymal stromal cells, dendritic cells, or regulatory T cells were studied between 2000 and 2021. Individual sources of evidence were evaluated critically, and the strength of evidence and risk of bias for each outcome of the transplant tolerance study were assessed. RESULTS From 28,173 citations, 245 studies were retrieved after suitable exclusion and duplicate removal. Of these, 22 studies (2 RCTs, 11 cohort studies, 6 case-control studies, and 3 case reports) explicitly related to both interventions (chimerism- and non-chimerism-based immune tolerance) were used in the final review process and were critically appraised. According to the findings, chimerism-based strategies fostered immunotolerance, allowing for the safe withdrawal of immunosuppressive medications. Cell-based therapy, on the other hand, frequently did not induce tolerance except for minimising immunosuppression. As a result, the rejection rates, renal allograft function, and survival rates could not be directly compared between these two groups. While chimerism-based tolerance protocols posed safety concerns due to myelosuppression, including infections and graft-versus-host disease, cell-based strategies lacked these adverse effects and were largely safe. There was a lack of direct comparisons between HLA-identical and HLA-disparate recipients, and the cost implications were not examined in several of the retrieved studies. Most studies reported successful immunosuppressive weaning lasting at least 3 years (ranging up to 11.4 years in some studies), particularly with chimerism-based therapy, while only a few investigators used immune surveillance techniques. The studies reviewed were often limited by selection, classification, ascertainment, performance, and attrition bias. CONCLUSIONS This review demonstrates that chimerism-based hematopoietic strategies induce immune tolerance, and a substantial number of patients are successfully weaned off immunosuppression. Despite the risk of complications associated with myelosuppression. Non-chimerism-based, non-hematopoietic cell protocols, on the other hand, have been proven to facilitate immunosuppression minimization but seldom elicit immunological tolerance. However, the results of this review must be interpreted with caution because of the non-randomised study design, potential confounding, and small sample size of the included studies. Further validation and refinement of tolerogenic protocols in accordance with local practice preferences is also warranted, with an emphasis on patient selection, cost ramifications, and immunological surveillance based on reliable tolerance assays.
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Affiliation(s)
- Chandrashekar Annamalai
- Postgraduate School of Medicine, Institute of Teaching and Learning, Faculty of Health and Life Sciences, University of Liverpool, UK.
| | - Vivek Kute
- Nephrology and Transplantation, Institute of Kidney Diseases and Research Center and Dr. H L Trivedi Institute of Transplantation Sciences (IKDRC-ITS), Ahmedabad, India
| | - Carl Sheridan
- Department of Eye and Vision Science, Ocular Cell Transplantation, Faculty of Health and Life Sciences, University of Liverpool, UK
| | - Ahmed Halawa
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Gilbo N, Blondeel J, Pirenne J, Romagnoli R, Camussi G, Monbaliu D. Organ Repair and Regeneration During Ex Situ Dynamic Preservation: The Future is Nano. Transpl Int 2023; 36:11947. [PMID: 38020754 PMCID: PMC10667440 DOI: 10.3389/ti.2023.11947] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/24/2023] [Indexed: 12/01/2023]
Abstract
Organ preservation and assessment with machine perfusion (MP) has provided transplant physicians with the ability to evaluate and select grafts suitable for transplantation. Nevertheless, the discard of organs considered too damaged still sustains the imbalance between donor organs supply and demands. Therefore, there is the pressing clinical need for strategies to repair and/or regenerate organs before transplantation, and MP is uniquely positioned to satisfy this need. The systemic administration of mesenchymal stromal cells (MSC) was shown to reduce ischemia-reperfusion injury in pre-clinical organ transplant models but could not be reproduced in clinical transplantation, largely because of inefficient cell delivery. The administration of MSC during MP is one strategy that recently gained much attention as an alternative delivery method to target MSC directly to the donor organ. However, careful reinterpretation of preliminary results reveals that this approach is equally limited by a suboptimal delivery of short-lived MSC to the target organ. In contrast, the use of MSC secretome and/or extracellular vesicles therapy during MP seems to be more efficient in harnessing MSC properties during MP. In this mini review we speculate on the future of the novel niche of ex situ organ repair and regeneration before transplantation.
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Affiliation(s)
- Nicholas Gilbo
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, Faculty of Medicine, KU Leuven, Leuven, Belgium
- University Hospital of Liège, Liège, Belgium
| | - Joris Blondeel
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, Faculty of Medicine, KU Leuven, Leuven, Belgium
- University Hospitals Leuven, Leuven, Belgium
| | - Jacques Pirenne
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, Faculty of Medicine, KU Leuven, Leuven, Belgium
- University Hospitals Leuven, Leuven, Belgium
| | - Renato Romagnoli
- General Surgery 2U–Liver Transplant Unit, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
- Dipartimento di Chirurgia Generale e Specialistica, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, School of Medicine, University of Turin, Turin, Italy
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, School of Medicine, University of Turin, Torino, Italy
| | - Diethard Monbaliu
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, Faculty of Medicine, KU Leuven, Leuven, Belgium
- University Hospitals Leuven, Leuven, Belgium
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Dreyer GJ, Drabbels JJM, de Fijter JW, van Kooten C, Reinders MEJ, Heidt S. Cell-free DNA measurement of three genomes after allogeneic MSC therapy in kidney transplant recipients indicates early cell death of infused MSC. Front Immunol 2023; 14:1240347. [PMID: 38022634 PMCID: PMC10652747 DOI: 10.3389/fimmu.2023.1240347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 09/22/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Mesenchymal stromal cell (MSC) therapy is a promising treatment that allows for drug minimization in clinical kidney transplantation. While it is thought that MSCs rapidly go into apoptosis after infusion, clinical evidence for this is scarce since methods to detect cell death of infused cells in vivo are lacking. Cell-free DNA (cfDNA) has recently gained attention as a biomarker for cell death. Methods In this study, we longitudinally measured cfDNA in plasma samples of the recipient, kidney donor, and allogeneic third-party MSC in the context of the Neptune study. cfDNA levels were measured at several time points before and after allogeneic MSC infusion in the 10 recipients who participated in the Neptune study. cfDNA ratios between the recipient, kidney graft, and MSC were determined. Results We observed a peak in MSC-derived cfDNA 4 h after the first and second infusions, after which MSC-derived cfDNA became undetectable. Generally, kidney graft-derived cfDNA remained in the baseline-level range. Discussion Our results support preclinical data that MSC are short-lived after infusion, also in a clinical in vivo setting, and are relevant for further research into the mechanism of action of MSC therapy.
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Affiliation(s)
- Geertje J. Dreyer
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, Netherlands
| | - Jos JM. Drabbels
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Johan W. de Fijter
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, Netherlands
| | - Cees van Kooten
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, Netherlands
| | - Marlies EJ. Reinders
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, Netherlands
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, Netherlands
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Siemionow M, Cwykiel J, Brodowska S, Chambily L. Human Multi-Chimeric Cell (HMCC) Therapy as a Novel Approach for Tolerance Induction in Transplantation. Stem Cell Rev Rep 2023; 19:2741-2755. [PMID: 37603137 PMCID: PMC10661767 DOI: 10.1007/s12015-023-10608-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2023] [Indexed: 08/22/2023]
Abstract
Cellular therapies are regarded as the most promising approach for inducing transplant tolerance without life-long immunosuppression in solid organ and vascularized composite allotransplantation (VCA). Currently, no therapies are achieving this goal. This study introduces a novel Human Multi-Chimeric Cell (HMCC) line created by fusion of umbilical cord blood (UCB) cells, from three unrelated donors as an alternative therapeutic approach to bone marrow transplantation and tolerance induction in solid organ and VCA transplants. We performed eighteen ex vivo polyethylene glycol mediated fusions of human UCB cells from three unrelated donors to create HMCC. Mononuclear cells labeled with PKH26, PKH67, and eFluor™ 670 fluorescent dyes were fused and sorted creating a new population of triple-labeled (PKH26/PKH67/eFluor™ 670) HMCC. The creation of HMCC from three unrelated human UCB donors was confirmed by flow cytometry and confocal microscopy. Genotyping analyses determined the tri-chimeric state of HMCC by presence of parent alleles and selected loci specific for each of three UCB donors. Phenotype characterization confirmed hematopoietic markers distribution, comparable to UCB donors. HMCC maintained viability and displayed a low apoptosis level. The COMET assay revealed absence of genotoxicity, confirming fusion safety. Colony forming units assay showed clonogenic properties of HMCC. This study confirmed the feasibility of HMCC creation from three unrelated human UCB donors and characterized tri-chimeric state, hematopoietic phenotype, viability, safety, and clonogenic properties of HMCC. The created HMCC line, representing genotype characteristics of three unrelated human UCB donors, introduces a novel therapeutic approach for bone marrow, solid organ, and VCA transplants.
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Affiliation(s)
- Maria Siemionow
- Department of Traumatology, Orthopaedics and Hand Surgery, Poznan University of Medical Sciences, Poznan, Poland.
- Department of Orthopaedics, University of Illinois at Chicago, 900 South Ashland Ave., Room# 3356, Molecular Biology Research Building, Chicago, IL, 60607, USA.
| | - Joanna Cwykiel
- Department of Orthopaedics, University of Illinois at Chicago, 900 South Ashland Ave., Room# 3356, Molecular Biology Research Building, Chicago, IL, 60607, USA
| | - Sonia Brodowska
- Department of Orthopaedics, University of Illinois at Chicago, 900 South Ashland Ave., Room# 3356, Molecular Biology Research Building, Chicago, IL, 60607, USA
| | - Lucile Chambily
- Department of Orthopaedics, University of Illinois at Chicago, 900 South Ashland Ave., Room# 3356, Molecular Biology Research Building, Chicago, IL, 60607, USA
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Vivarelli M, Colucci M, Algeri M, Zotta F, Emma F, L’Erario I, Busutti M, Rota S, Capelli C, Introna M, Todeschini M, Casiraghi F, Perna A, Peracchi T, De Salvo A, Rubis N, Locatelli F, Remuzzi G, Ruggenenti P. A phase I study of autologous mesenchymal stromal cells for severe steroid-dependent nephrotic syndrome. JCI Insight 2023; 8:e169424. [PMID: 37561590 PMCID: PMC10561718 DOI: 10.1172/jci.insight.169424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 08/08/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUNDSevere forms of idiopathic nephrotic syndrome (INS) require prolonged immunosuppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects.METHODSWe performed a phase I open-label trial assessing safety and feasibility of autologous bone marrow-derived MSCs (BM-MSCs) in children and young adults with severe forms of steroid-dependent nephrotic syndrome. Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy, and immunomodulatory effects in vivo were monitored for 12 months.RESULTSSixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (P = 0.02) and number of relapses was reduced (P = 0.002) after BM-MSC infusion, compared with the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared with baseline (P < 0.05). No treatment benefit was observed in adults.In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction in total CD19+, mature, and memory B cells and an increase in regulatory T cells in vivo up to 3-6 months following BM-MSC infusionCONCLUSIONTreatment with autologous BM-MSCs is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3-6 months may sustain benefit.TRIAL REGISTRATIONEudraCT 2016-004804-77.FUNDINGAIFA Ricerca Indipendente 2016-02364623.
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Affiliation(s)
- Marina Vivarelli
- Division of Nephrology, and
- Laboratory of Nephrology, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | - Manuela Colucci
- Laboratory of Nephrology, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | - Mattia Algeri
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | | | | | | | | | - Stefano Rota
- Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale (ASST), Bergamo, Italy
| | - Chiara Capelli
- Center of Cellular Therapy “G. Lanzani,” Haematology Department, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Martino Introna
- Center of Cellular Therapy “G. Lanzani,” Haematology Department, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Marta Todeschini
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | | | - Annalisa Perna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Tobia Peracchi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Andrea De Salvo
- Psychology Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | - Nadia Rubis
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Franco Locatelli
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
- Catholic University of the Sacred Heart, Rome, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Piero Ruggenenti
- Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale (ASST), Bergamo, Italy
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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13
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Kahrizi MS, Mousavi E, Khosravi A, Rahnama S, Salehi A, Nasrabadi N, Ebrahimzadeh F, Jamali S. Recent advances in pre-conditioned mesenchymal stem/stromal cell (MSCs) therapy in organ failure; a comprehensive review of preclinical studies. Stem Cell Res Ther 2023; 14:155. [PMID: 37287066 DOI: 10.1186/s13287-023-03374-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 05/10/2023] [Indexed: 06/09/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs)-based therapy brings the reassuring capability to regenerative medicine through their self-renewal and multilineage potency. Also, they secret a diversity of mediators, which are complicated in moderation of deregulated immune responses, and yielding angiogenesis in vivo. Nonetheless, MSCs may lose biological performance after procurement and prolonged expansion in vitro. Also, following transplantation and migration to target tissue, they encounter a harsh milieu accompanied by death signals because of the lack of proper tensegrity structure between the cells and matrix. Accordingly, pre-conditioning of MSCs is strongly suggested to upgrade their performances in vivo, leading to more favored transplantation efficacy in regenerative medicine. Indeed, MSCs ex vivo pre-conditioning by hypoxia, inflammatory stimulus, or other factors/conditions may stimulate their survival, proliferation, migration, exosome secretion, and pro-angiogenic and anti-inflammatory characteristics in vivo. In this review, we deliver an overview of the pre-conditioning methods that are considered a strategy for improving the therapeutic efficacy of MSCs in organ failures, in particular, renal, heart, lung, and liver.
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Affiliation(s)
| | - Elnaz Mousavi
- Department of Endodontics, School of Dentistry, Guilan University of Medical Sciences, Rasht, Iran
| | - Armin Khosravi
- Department of Periodontics, Dental School, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Sara Rahnama
- Department of Pediatric Dentistry, School of Dentistry, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Salehi
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Navid Nasrabadi
- Department of Endodontics, School of Dentistry, Birjand University of Medical Sciences, Birjand, Iran
| | - Farnoosh Ebrahimzadeh
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Samira Jamali
- Department of Endodontics, Stomatological Hospital, College of Stomatology, Xi'an Jiaotong University, Shaanxi, People's Republic of China.
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14
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Santarsiero D, Aiello S. The Complement System in Kidney Transplantation. Cells 2023; 12:cells12050791. [PMID: 36899927 PMCID: PMC10001167 DOI: 10.3390/cells12050791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.
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15
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Miceli V, Bulati M, Gallo A, Iannolo G, Busà R, Conaldi PG, Zito G. Role of Mesenchymal Stem/Stromal Cells in Modulating Ischemia/Reperfusion Injury: Current State of the Art and Future Perspectives. Biomedicines 2023; 11:689. [PMID: 36979668 PMCID: PMC10045387 DOI: 10.3390/biomedicines11030689] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/15/2023] [Accepted: 02/21/2023] [Indexed: 02/26/2023] Open
Abstract
Ischemia/reperfusion injury (IRI) is a multistep damage that occurs in several tissues when a blood flow interruption is inevitable, such as during organ surgery or transplantation. It is responsible for cell death and tissue dysfunction, thus leading, in the case of transplantation, to organ rejection. IRI takes place during reperfusion, i.e., when blood flow is restored, by activating inflammation and reactive oxygen species (ROS) production, causing mitochondrial damage and apoptosis of parenchymal cells. Unfortunately, none of the therapies currently in use are definitive, prompting the need for new therapeutic approaches. Scientific evidence has proven that mesenchymal stem/stromal cells (MSCs) can reduce inflammation and ROS, prompting this cellular therapy to also be investigated for treatment of IRI. Moreover, it has been shown that MSC therapeutic effects were mediated in part by their secretome, which appears to be involved in immune regulation and tissue repair. For these reasons, mediated MSC paracrine function might be key for injury amelioration upon IRI damage. In this review, we highlight the scientific literature on the potential beneficial use of MSCs and their products for improving IRI outcomes in different tissues/organs, focusing in particular on the paracrine effects mediated by MSCs, and on the molecular mechanisms behind these effects.
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Affiliation(s)
- Vitale Miceli
- Research Department, IRCSS ISMETT (Istituto Mediterraneo per I Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | | | | | | | | | | | - Giovanni Zito
- Research Department, IRCSS ISMETT (Istituto Mediterraneo per I Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
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16
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Mesenchymal Stem Cell Transplantation Ameliorates Ara-C-Induced Motor Deficits in a Mouse Model of Cerebellar Ataxia. J Clin Med 2023; 12:jcm12051756. [PMID: 36902541 PMCID: PMC10003478 DOI: 10.3390/jcm12051756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 02/25/2023] Open
Abstract
This study investigated the therapeutic effects of transplanting human mesenchymal stem cells (hMSCs) into wild-type mice that were intraperitoneally administered cytosine arabinoside (Ara-C) to develop cerebellar ataxia (CA) during the first three postnatal days. hMSCs were intrathecally injected into 10-week-old mice once or thrice at 4-week intervals. Compared to the nontreated mice, the hMSC-treated mice showed improved motor and balance coordination, as measured using the rotarod, open-field, and ataxic scoring assessments, and increased protein levels in Purkinje and cerebellar granule cells, as measured using calbindin and NeuN protein markers. Multiple hMSC injections preserved Ara-C-induced cerebellar neuronal loss and improved cerebellar weight. Furthermore, the hMSC implantation significantly elevated the levels of neurotrophic factors, including brain-derived and glial cell line-derived neurotrophic factors, and suppressed TNF-α-, IL-1β-, and iNOS-mediated proinflammatory responses. Collectively, our results demonstrate that hMSCs exhibit therapeutic potential for Ara-C-induced CA by protecting neurons through the stimulation of neurotrophic factors and inhibition of cerebellar inflammatory responses, which can improve motor behavior and alleviate ataxia-related neuropathology. In summary, this study suggests that hMSC administration, particularly multiple treatments, can effectively treat ataxia-related symptoms with cerebellar toxicity.
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17
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Večerić-Haler Ž, Sever M, Kojc N, Halloran PF, Boštjančič E, Mlinšek G, Oblak M, Poženel P, Švajger U, Hartman K, Kneževič M, Barlič A, Girandon L, Aleš Rigler A, Zver S, Buturović Ponikvar J, Arnol M. Autologous Mesenchymal Stem Cells for Treatment of Chronic Active Antibody-Mediated Kidney Graft Rejection: Report of the Phase I/II Clinical Trial Case Series. Transpl Int 2022; 35:10772. [PMID: 36484064 PMCID: PMC9722440 DOI: 10.3389/ti.2022.10772] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 11/08/2022] [Indexed: 11/23/2022]
Abstract
Mesenchymal stem cell (MSCs) therapy has already been studied in kidney transplant recipients (KTRs), and the available data showed that it is safe and well tolerated. The aim of this study was to evaluate the safety and efficacy of autologous MSCs in combination with standard therapy in KTRs with biopsy-proven chronic active antibody-mediated rejection (AMR). Patients with biopsy-proven chronic active AMR received treatment with autologous bone marrow-derived MSCs (3 × 106 cells/kg iv) after completion of standard therapy and were followed for up to 12 months. The primary endpoints were safety by assessment of adverse events. Secondary endpoints included assessment of kidney graft function, immunological and histological changes related to AMR activity and chronicity assessed by conventional microscopy and molecular transcripts. A total of 3 patients were enrolled in the study before it was terminated prematurely because of adverse events. We found that AMR did not improve in any of the patients after treatment with MSCs. In addition, serious adverse events were observed in one case when autologous MSCs therapy was administered in the late phase after kidney transplantation, which requires further elucidation.
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Affiliation(s)
- Željka Večerić-Haler
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,*Correspondence: Željka Večerić-Haler,
| | - Matjaž Sever
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,Department of Haematology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Nika Kojc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Philip F. Halloran
- Division of Nephrology and Transplant Immunology, Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, AB, Canada
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Gregor Mlinšek
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Manca Oblak
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Primož Poženel
- Division for Cells and Tissue, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
| | - Urban Švajger
- Division for Cells and Tissue, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
| | - Katrina Hartman
- Division for Cells and Tissue, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
| | | | - Ariana Barlič
- Educell d.o.o Cell Therapy Service, Ljubljana, Slovenia
| | | | - Andreja Aleš Rigler
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Samo Zver
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,Department of Haematology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Jadranka Buturović Ponikvar
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Miha Arnol
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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18
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Shimoyama K, Tsuchiya T, Watanabe H, Ergalad A, Iwatake M, Miyazaki T, Hashimoto Y, Hsu YI, Hatachi G, Matsumoto K, Ishii M, Mizoguchi S, Doi R, Tomoshige K, Yamaoka T, Nagayasu T. Donor and Recipient Adipose-Derived Mesenchymal Stem Cell Therapy for Rat Lung Transplantation. Transplant Proc 2022; 54:1998-2007. [PMID: 36041932 DOI: 10.1016/j.transproceed.2022.05.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 05/03/2022] [Accepted: 05/22/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are beginning to be proven as immunosuppressant in the field of organ transplantation. However, the effects of MSC origin (donor or recipient) on immunosuppression are not clear. Hence, we investigated the effects of recipient and donor adipose-derived MSCs (ADMSCs) on immunosuppression in a rat lung transplantation model. METHODS Subjects were divided into no treatment, tacrolimus administration, recipient ADMSC administration, donor ADMSC administration, and mixed donor and recipient ADMSC administration groups. ADMSC-administered groups were also treated with tacrolimus. Histologic study, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, and polymerase chain reaction were used for various analyses. RESULTS Fluorescently labeled ADMSCs were predominant in the grafted donor lung, but not in the recipient lung, on day 5. On day 7, the pathologic rejection grades of the grafted donor lung were significantly lower in the ADMSC-administered groups (P < .05) and did not differ among these groups. Although serum hepatocyte growth factor and vascular endothelial growth factor levels did not differ among the groups, interleukin 10 level was slightly higher in the ADMSC-administered groups. The numbers of infiltrating regulatory T cells in the grafted lung were significantly higher in the ADMSC-administered groups (P < .05) but did not differ with cell origin. Transcriptional analysis suggested interleukin 6 suppression to be the main overlapping immunosuppressive mechanism, regardless of origin. Therefore, a donor or recipient origin may not influence the immunosuppressive efficacy of ADMSCs in our rat lung transplantation model. CONCLUSIONS Collectively, the results indicate that allogenic ADMSCs, regardless of their origin, may exert similar immunosuppressive effects in clinical organ transplantation.
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Affiliation(s)
- Koichiro Shimoyama
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomoshi Tsuchiya
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Division of Nucleic Acid Drug Development, Research Institute for Science and Technology, Tokyo University of Science, Chiba, Japan.
| | - Hironosuke Watanabe
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Abdelmotagaly Ergalad
- Center for Preclinical Surgical and Interventional Research, Texas Heart Institute, Houston, Texas
| | - Mayumi Iwatake
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takuro Miyazaki
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yasumasa Hashimoto
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yu-I Hsu
- Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Go Hatachi
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Keitaro Matsumoto
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mitsutoshi Ishii
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Satoshi Mizoguchi
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ryoichiro Doi
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Koichi Tomoshige
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tetsuji Yamaoka
- Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Takeshi Nagayasu
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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19
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Qin H, Sun C, Zhu Y, Qin Y, Ren S, Wang Z, Li C, Li X, Zhang B, Hao J, Li G, Wang H, Shao B, Zhang J, Wang H. IL-37 overexpression promotes endometrial regenerative cell-mediated inhibition of cardiac allograft rejection. Stem Cell Res Ther 2022; 13:302. [PMID: 35841010 PMCID: PMC9284885 DOI: 10.1186/s13287-022-02982-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 04/19/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Endometrial regenerative cells (ERCs) play an important role in attenuation of acute allograft rejection, while their effects are limited. IL-37, a newly discovered immunoregulatory cytokine of the IL-1 family, can regulate both innate and adaptive immunity. Whether IL-37 overexpression can enhance the therapeutic effects of ERCs in inhibition of acute cardiac allograft rejection remains unknown and will be explored in this study. METHODS C57BL/6 mice recipients receiving BALB/c mouse heterotopic heart allografts were randomly divided into the phosphate-buffered saline (untreated), ERC treated, negative lentiviral control ERC (NC-ERC) treated, and IL-37 overexpressing ERC (IL-37-ERC) treated groups. Graft pathological changes were assessed by H&E staining. The intra-graft cell infiltration and splenic immune cell populations were analyzed by immunohistochemistry and flow cytometry, respectively. The stimulatory property of recipient DCs was tested by an MLR assay. Furthermore, serum cytokine profiles of recipients were measured by ELISA assay. RESULTS Mice treated with IL-37-ERCs achieved significantly prolonged allograft survival compared with the ERC-treated group. Compared with all the other control groups, IL-37-ERC-treated group showed mitigated inflammatory response, a significant increase in tolerogenic dendritic cells (Tol-DCs), regulatory T cells (Tregs) in the grafts and spleens, while a reduction of Th1 and Th17 cell population. Additionally, there was a significant upregulation of immunoregulatory IL-10, while a reduction of IFN-γ, IL-17A, IL-12 was detected in the sera of IL-37-ERC-treated recipients. CONCLUSION IL-37 overexpression can promote the therapeutic effects of ERCs to inhibit acute allograft rejection and further prolong graft survival. This study suggests that gene-modified ERCs overexpressing IL-37 may pave the way for novel therapeutic options in the field of transplantation.
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Affiliation(s)
- Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Chenglu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Yanglin Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Yafei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Shaohua Ren
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Zhaobo Wang
- School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Chuan Li
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Baoren Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Jingpeng Hao
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China.,Department of Anorectal Surgery, Tianjin Medical University Second Hospital, Tianjin, China
| | - Guangming Li
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Hongda Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Bo Shao
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Jingyi Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China. .,Tianjin General Surgery Institute, Tianjin, China.
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20
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Creamer DG, Schmiedt CW, Bullington AC, Caster CM, Schmiedt JM, Hurley DJ, Berghaus RD. Influence of exposure to microbial ligands, immunosuppressive drugs and chronic kidney disease on endogenous immunomodulatory gene expression in feline adipose-derived mesenchymal stem cells. J Feline Med Surg 2022; 24:e43-e56. [PMID: 35302413 PMCID: PMC11104253 DOI: 10.1177/1098612x221083074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Feline autologous mesenchymal stem cells (MSCs) show promise for immunomodulatory activity, but the functional impact of chronic kidney disease (CKD), concurrent immunosuppressive drug administration or infection is unknown. The study objectives compare endogenous cytokine gene expression (interleukin [IL]-6, IL-10, IL-12p40, IL-18 and transforming growth factor beta [TGF-β]) in adipose-derived MSCs (aMSCs) from cats with and without CKD, following in vitro exposure to microbial ligands and treatment with common immunosuppressive drugs. METHODS Previously obtained aMSCs, phenotype CD44+, CD90+, CD105+ and MHCII-, from cats with (n = 6) and without (n = 6) CKD were compared via real-time PCR (RT-PCR) for immunomodulatory gene expression. aMSCs were exposed in vitro to lipopolysaccharide (LPS), peptidoglycan or polyinosinic:polycytidylic acid (Poly I:C), simulating bacterial or viral exposure, respectively. aMSCs were also exposed to ciclosporin, dexamethasone or methotrexate. Gene expression was measured using RT-PCR, and Cq was utilized after each run to calculate the delta cycle threshold. RESULTS aMSCs isolated from healthy and CKD cats showed no significant differences in gene expression in the five measured cytokines. No significant changes in measured gene expression after drug treatment or microbial ligand stimulation were observed between normal or CKD affected cats. Proinflammatory genes (IL-6, IL-12p40 and IL-18) showed altered expression in aMSCs from both groups when compared with the same cells in standard culture after exposure to methotrexate. Poly I:C altered IL-6 and TGF-β gene expression in aMSCs from both healthy and CKD cats when compared with the same cells in standard culture. CONCLUSIONS AND RELEVANCE The five genes tested showed no statistical differences between aMSCs from healthy or CKD cats. There was altered cytokine gene expression between the control and treatment groups of both healthy and CKD cats suggesting feline aMSCs have altered function with immunosuppressive treatment or microbial ligand exposure. Although the current clinical relevance of this pilot study comparing brief exposure to select agents in vitro in aMSCs from a small number of cats is unknown, the study highlights a need for continued investigation into the effects of disease and concurrent therapies on use of cell-based therapies in feline patients.
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Affiliation(s)
- Danielle G Creamer
- Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - Chad W Schmiedt
- Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - Anna Claire Bullington
- Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - Courtney M Caster
- Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - Jennifer M Schmiedt
- Department of Population Health, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - David J Hurley
- Department of Population Health, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - Roy D Berghaus
- Department of Population Health, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
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21
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Mönch D, Reinders MEJ, Dahlke MH, Hoogduijn MJ. How to Make Sense out of 75,000 Mesenchymal Stromal Cell Publications? Cells 2022; 11:cells11091419. [PMID: 35563725 PMCID: PMC9101744 DOI: 10.3390/cells11091419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stromal cells have been the subject of an expanding number of studies over the past decades. Today, over 75,000 publications are available that shine light on the biological properties and therapeutic effects of these versatile cells in numerous pre-clinical models and early-phase clinical trials. The massive number of papers makes it hard for researchers to comprehend the whole field, and furthermore, they give the impression that mesenchymal stromal cells are wonder cells that are curative for any condition. It is becoming increasingly difficult to dissect how and for what conditions mesenchymal stromal cells exhibit true and reproducible therapeutic effects. This article tries to address the question how to make sense of 75,000, and still counting, publications on mesenchymal stromal cells.
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Affiliation(s)
- Dina Mönch
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany;
- University of Tübingen, 72074 Tübingen, Germany
| | - Marlies E. J. Reinders
- Erasmus MC Transplant Institute, Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands;
| | - Marc H. Dahlke
- Department of Surgery, Robert-Bosch-Hospital, 70376 Stuttgart, Germany;
| | - Martin J. Hoogduijn
- Erasmus MC Transplant Institute, Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands;
- Correspondence:
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22
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Deo D, Marchioni M, Rao P. Mesenchymal Stem/Stromal Cells in Organ Transplantation. Pharmaceutics 2022; 14:pharmaceutics14040791. [PMID: 35456625 PMCID: PMC9029865 DOI: 10.3390/pharmaceutics14040791] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 02/07/2023] Open
Abstract
Organ transplantation is essential and crucial for saving and enhancing the lives of individuals suffering from end-stage organ failure. Major challenges in the medical field include the shortage of organ donors, high rates of organ rejection, and long wait times. To address the current limitations and shortcomings, cellular therapy approaches have been developed using mesenchymal stem/stromal cells (MSC). MSC have been isolated from various sources, have the ability to differentiate to important cell lineages, have anti-inflammatory and immunomodulatory properties, allow immunosuppressive drug minimization, and induce immune tolerance towards the transplanted organ. Additionally, rapid advances in the fields of tissue engineering and regenerative medicine have emerged that focus on either generating new organs and organ sources or maximizing the availability of existing organs. This review gives an overview of the various properties of MSC that have enabled its use as a cellular therapy for organ preservation and transplant. We also highlight emerging fields of tissue engineering and regenerative medicine along with their multiple sub-disciplines, underlining recent advances, widespread clinical applications, and potential impact on the future of tissue and organ transplantation.
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23
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Mesenchymal Stromal Cells Mediate Clinically Unpromising but Favourable Immune Responses in Kidney Transplant Patients. Stem Cells Int 2022; 2022:2154544. [PMID: 35211176 PMCID: PMC8863486 DOI: 10.1155/2022/2154544] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 01/11/2022] [Indexed: 01/22/2023] Open
Abstract
Background Allograft rejection postkidney transplantation (KTx) is a major clinical challenge despite increased access to a healthcare system and improvement in immunosuppressive (IS) drugs. In recent years, mesenchymal stromal cells (MSCs) have aroused considerable interest in field of transplantation due to their immunomodulatory and regenerative properties. This study was aimed at investigating safety, feasibility, and immunological effects of autologous MSCs (auto-MSCs) and allogeneic MSCs (allo-MSCs) as a complement to IS drug therapy in KTx patients. Methods 10 patients undergoing KTx with a living-related donor were analysed along with 5 patients in the control group. Patients were given auto-MSCs or allo-MSCs at two time points, i.e., one day before transplant (D-0) and 30 days after transplant (D-30) at the rate of 1.0-1.5 × 106 MSCs per kg body weight in addition to immunosuppressants. Patients were followed up for 2 years, and 29 immunologically relevant lymphocyte subsets and 8 cytokines and important biomarkers were analysed at all time points. Results Patients displayed no signs of discomfort or dose-related toxicities in response to MSC infusion. Flow cytometric analysis revealed an increase in B regulatory lymphocyte populations and nonconventional T regulatory cells and a decrease in T effector lymphocyte proportions in auto-MSC-infused patients. No such favourable immune responses were observed in all MSC-infused patients. Conclusion This study provides evidence that auto-MSCs are safe and well tolerated. This is the first ever report to compare autologous and allogeneic MSC infusion in KTx patients. Importantly, our data demonstrated that MSC-induced immune responses in patients did not completely correlate with clinical outcomes. Our findings add to the current perspective of using MSCs in KTx and explore possibilities through which donor/recipient chimerism can be achieved to induce immune tolerance in KTx patients.
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24
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Capelli C, Frigerio S, Lisini D, Nava S, Gaipa G, Belotti D, Cabiati B, Budelli S, Lazzari L, Bagnarino J, Tanzi M, Comoli P, Perico N, Introna M, Golay J. A comprehensive report of long-term stability data for a range ATMPs: A need to develop guidelines for safe and harmonized stability studies. Cytotherapy 2022; 24:544-556. [PMID: 35177338 DOI: 10.1016/j.jcyt.2021.12.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 12/01/2021] [Accepted: 12/06/2021] [Indexed: 11/03/2022]
Abstract
BACKGROUND AIMS Advanced therapy medicinal products (ATMPs) are novel drugs based on genes, cells or tissues developed to treat many different diseases. Stability studies of each new ATMP need to be performed to define its shelf life and guarantee efficacy and safety upon infusion, and these are presently based on guidelines originally drafted for standard pharmaceutical drugs, which have properties and are stored in conditions quite different from cell products. The aim of this report is to provide evidence-based information for stability studies on ATMPs that will facilitate the interlaboratory harmonization of practices in this area. METHODS We have collected and analyzed the results of stability studies on 19 different cell-based experimental ATMPs, produced by five authorized cell factories forming the Lombardy "Plagencell network" for use in 36 approved phase I/II clinical trials; most were cryopreserved and stored in liquid nitrogen vapors for 1 to 13 years. RESULTS The cell attributes collected in stability studies included cell viability, immunophenotype and potency assays, in particular immunosuppression, cytotoxicity, cytokine release and proliferation/differentiation capacity. Microbiological attributes including sterility, endotoxin levels and mycoplasma contamination were also analyzed. All drug products (DPs), cryopreserved in various excipients containing 10% DMSO and in different primary containers, were very stable long term at <-150°C and did not show any tendency for diminished viability or efficacy for up to 13.5 years. CONCLUSIONS Our data indicate that new guidelines for stability studies, specific for ATMPs and based on risk analyses, should be drafted to harmonize practices, significantly reduce the costs of stability studies without diminishing safety. Some specific suggestions are presented in the discussion.
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Affiliation(s)
- Chiara Capelli
- Center of Cellular Therapy "G. Lanzani", ASST Papa Giovanni XXIII, Bergamo, Italy; Fondazione per la Ricerca Ospedale di Bergamo, Bergamo, Italy
| | - Simona Frigerio
- Cell Therapy Production Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Daniela Lisini
- Cell Therapy Production Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Sara Nava
- Cell Therapy Production Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Giuseppe Gaipa
- Laboratory of Cell and Gene Therapy Stefano Verri, ASST Monza Ospedale San Gerardo, Monza, Italy
| | - Daniela Belotti
- Laboratory of Cell and Gene Therapy Stefano Verri, ASST Monza Ospedale San Gerardo, Monza, Italy
| | - Benedetta Cabiati
- Laboratory of Cell and Gene Therapy Stefano Verri, ASST Monza Ospedale San Gerardo, Monza, Italy
| | - Silvia Budelli
- Laboratory of Regenerative Medicine - Cell Factory, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Lorenza Lazzari
- Laboratory of Regenerative Medicine - Cell Factory, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Jessica Bagnarino
- UOSD Cell Factory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Matteo Tanzi
- UOSD Cell Factory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Patrizia Comoli
- UOSD Cell Factory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Norberto Perico
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Martino Introna
- Center of Cellular Therapy "G. Lanzani", ASST Papa Giovanni XXIII, Bergamo, Italy.
| | - Josée Golay
- Center of Cellular Therapy "G. Lanzani", ASST Papa Giovanni XXIII, Bergamo, Italy; Fondazione per la Ricerca Ospedale di Bergamo, Bergamo, Italy
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25
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Meucci MC, Reinders MEJ, Groeneweg KE, Bezstarosti S, Ajmone Marsan N, Bax JJ, De Fijter JW, Delgado V. Cardiovascular Effects of Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Therapy With Early Tacrolimus Withdrawal in Renal Transplant Recipients: An Analysis of the Randomized TRITON Study. J Am Heart Assoc 2021; 10:e023300. [PMID: 34913362 PMCID: PMC9075245 DOI: 10.1161/jaha.121.023300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background After renal transplantation, there is a need of immunosuppressive regimens that effectively prevent allograft rejection while minimizing cardiovascular complications. This substudy of the TRITON trial evaluated the cardiovascular effects of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in renal transplant recipients. Methods and Results Renal transplant recipients were randomized to MSC therapy, infused at weeks 6 and 7 after transplantation, with withdrawal at week 8 of tacrolimus or standard tacrolimus dose. Fifty-four patients (MSC group=27; control group=27) underwent transthoracic echocardiography at weeks 4 and 24 after transplantation and were included in this substudy. Changes in clinical and echocardiographic variables were compared. The MSC group showed a benefit in blood pressure control, assessed by a significant interaction between changes in diastolic blood pressure and the treatment group (P=0.005), and a higher proportion of patients achieving the predefined blood pressure target of <140/90 mm Hg compared with the control group (59.3% versus 29.6%, P=0.03). A significant reduction in left ventricular mass index was observed in the MSC group, whereas there were no changes in the control group (P=0.002). The proportion of patients with left ventricular hypertrophy decreased at 24 weeks in the MSC group (33.3% versus 70.4%, P=0.006), whereas no changes were noted in the control group (63.0% versus 48.1%, P=0.29). Additionally, MSC therapy prevented progressive left ventricular diastolic dysfunction, as demonstrated by changes in mitral deceleration time and tricuspid regurgitant jet velocity. Conclusions MSC strategy is associated with improved blood pressure control, regression of left ventricular hypertrophy, and prevention of progressive diastolic dysfunction at 24 weeks after transplantation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03398681.
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Affiliation(s)
- Maria Chiara Meucci
- Department of Cardiology Leiden University Medical Center Leiden the Netherlands.,Department of Cardiovascular and Thoracic Sciences Fondazione Policlinico Universitario A. Gemelli IRCCSCatholic University of the Sacred Heart Rome Italy
| | - Marlies E J Reinders
- Department of Internal Medicine (Nephrology) Leiden University Medical Center Leiden the Netherlands
| | - Koen E Groeneweg
- Department of Internal Medicine (Nephrology) Leiden University Medical Center Leiden the Netherlands
| | - Suzanne Bezstarosti
- Department of Internal Medicine (Nephrology) Leiden University Medical Center Leiden the Netherlands.,Department of Immunology Leiden University Medical Center Leiden the Netherlands
| | - Nina Ajmone Marsan
- Department of Cardiology Leiden University Medical Center Leiden the Netherlands
| | - Jeroen J Bax
- Department of Cardiology Leiden University Medical Center Leiden the Netherlands.,Heart Center University of Turku and Turku University Hospital Turku Finland
| | - Johan W De Fijter
- Department of Internal Medicine (Nephrology) Leiden University Medical Center Leiden the Netherlands
| | - Victoria Delgado
- Department of Cardiology Leiden University Medical Center Leiden the Netherlands
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26
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Wang X, Zhou C, Liu J, Mao L, Yang T, Hong X, Jiang N, Jia R. Administration of adipose stromal vascular fraction attenuates acute rejection in donation after circulatory death rat renal transplantation. Int J Urol 2021; 29:266-275. [PMID: 34908191 DOI: 10.1111/iju.14757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 11/11/2021] [Accepted: 11/16/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Stem cell therapy represents a new approach to induce immune tolerance in solid organ transplantation. However, the time-consuming process of stem cell expending limits the range of stem cell treatment. Uncultured adipose stromal vascular fraction is considered an attractive cell source for cell-based therapy. This study aimed to evaluate the effect of stromal vascular fraction on the immune system in donation after circulatory death rat renal transplantation. METHODS Stromal vascular fraction cells and splenocytes were co-cultured to evaluate the effect of stromal vascular fraction on splenocyte proliferation and viability. Sprague-Dawley rats were used as donors. and Wistar rats as recipients to establish a donation after a circulatory death rat renal transplantation model. Warm ischemia time was 5 min. Stromal vascular fraction was administered in the rat model following the intra-arterial route. The spleens and grafts of recipients were harvested on days 1, 3 and 7 post-transplantation for assessing acute rejection, infiltration of inflammatory cells, indoleamine 2, 3-dioxygenase expression and T-cell frequency in the spleen. RESULTS Stromal vascular fraction could inhibit proliferation and induce apoptosis of splenocytes in vitro (P < 0.05). The administration of stromal vascular fraction could significantly reduce acute rejection and infiltration of CD8+ T cells and mononuclear macrophages in grafts, and increase indoleamine 2, 3-dioxygenase expression (P < 0.05). The frequency of CD8+ T cells decreased, and the frequency of CD25+ Foxp3+ regulatory T cells increased in the spleen of the acute rejection + stromal vascular fraction group on day 7 post-transplantation (P < 0.05). CONCLUSION Administration of the adipose stromal vascular fraction could attenuate acute rejection in donation after circulatory death renal transplantation by increasing the ratio of regulatory T cells and enhancing indoleamine 2, 3-dioxygenase expression.
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Affiliation(s)
- Xinning Wang
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Center of Renal Transplantation, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Changcheng Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Center of Renal Transplantation, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jingyu Liu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Center of Renal Transplantation, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Liang Mao
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Center of Renal Transplantation, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Tianli Yang
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Center of Renal Transplantation, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xi Hong
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Center of Renal Transplantation, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Nan Jiang
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Center of Renal Transplantation, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ruipeng Jia
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Center of Renal Transplantation, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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27
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Preclinical Assessment of Mesenchymal-Stem-Cell-Based Therapies in Spinocerebellar Ataxia Type 3. Biomedicines 2021; 9:biomedicines9121754. [PMID: 34944570 PMCID: PMC8698556 DOI: 10.3390/biomedicines9121754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies for neurodegenerative diseases, including spinocerebellar ataxias. Spinocerebellar ataxia type 3 (SCA3)—or Machado–Joseph disease (MJD)—is the most common dominant ataxia, being mainly characterized by motor deficits; however, SCA3/MJD has a complex and heterogeneous pathophysiology, involving many CNS brain regions, contributing to the lack of effective therapies. Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for CNS disorders. Beyond their differentiation potential, MSCs secrete a broad range of neuroregulatory factors that can promote relevant neuroprotective and immunomodulatory actions in different pathophysiological contexts. The objective of this work was to study the effects of (1) human MSC transplantation and (2) human MSC secretome (CM) administration on disease progression in vivo, using the CMVMJD135 mouse model of SCA3/MJD. Our results showed that a single CM administration was more beneficial than MSC transplantation—particularly in the cerebellum and basal ganglia—while no motor improvement was observed when these cell-based therapeutic approaches were applied in the spinal cord. However, the effects observed were mild and transient, suggesting that continuous or repeated administration would be needed, which should be further tested.
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28
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Shang Z, Jiang Y, Guan X, Wang A, Ma B. Therapeutic Effects of Stem Cells From Different Source on Renal Ischemia- Reperfusion Injury: A Systematic Review and Network Meta-analysis of Animal Studies. Front Pharmacol 2021; 12:713059. [PMID: 34539400 PMCID: PMC8444551 DOI: 10.3389/fphar.2021.713059] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/17/2021] [Indexed: 12/20/2022] Open
Abstract
Objective: Although stem cell therapy for renal ischemia-reperfusion injury (RIRI) has made immense progress in animal studies, conflicting results have been reported by the investigators. Therefore, we aimed to systematically evaluate the effects of different stem cells on renal function of animals with ischemia-reperfusion injury and to compare the efficacies of stem cells from various sources. Methods: PubMed, Web of Science, Embase, Cochrane, CNKI, VIP, CBM, and WanFang Data were searched for records until April 2021. Two researchers independently conducted literature screening, data extraction, and literature quality evaluation. Results and conclusion: Seventy-two animal studies were included for data analysis. Different stem cells significantly reduced serum creatinine and blood urea nitrogen levels in the early and middle stages (1 and 7 days) compared to the negative control group, however there was no significant difference in the late stage among all groups (14 days); In the early stage (1 day), the renal histopathological score in the stem cell group was significantly lower than that in the negative control group, and there was no significant difference among these stem cells. In addition, there was no significant difference between stem cell and negative control in proliferation of resident cells, however, significantly less apoptosis of resident cells than negative control. In conclusion, the results showed that stem cells from diverse sources could improve the renal function of RIRI animals. ADMSCs and MDMSCs were the most-researched stem cells, and they possibly hold the highest therapeutic potential. However, the quality of evidence included in this study is low, and there are many risks of bias. The exact efficacy of the stem cells and the requirement for further clinical studies remain unclear.
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Affiliation(s)
- Zhizhong Shang
- Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Yanbiao Jiang
- Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Xin Guan
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Anan Wang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Bin Ma
- Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
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29
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Calcat-i-Cervera S, Sanz-Nogués C, O'Brien T. When Origin Matters: Properties of Mesenchymal Stromal Cells From Different Sources for Clinical Translation in Kidney Disease. Front Med (Lausanne) 2021; 8:728496. [PMID: 34616756 PMCID: PMC8488400 DOI: 10.3389/fmed.2021.728496] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022] Open
Abstract
Advanced therapy medicinal products (ATMPs) offer new prospects to improve the treatment of conditions with unmet medical needs. Kidney diseases are a current major health concern with an increasing global prevalence. Chronic renal failure appears after many years of impairment, which opens a temporary window to apply novel therapeutic approaches to delay or halt disease progression. The immunomodulatory, anti-inflammatory, and pro-regenerative properties of mesenchymal stromal cells (MSCs) have sparked interest for their use in cell-based regenerative therapies. Currently, several early-phase clinical trials have been completed and many are ongoing to explore MSC safety and efficacy in a wide range of nephropathies. However, one of the current roadblocks to the clinical translation of MSC therapies relates to the lack of standardization and harmonization of MSC manufacturing protocols, which currently hinders inter-study comparability. Studies have shown that cell culture processing variables can have significant effects on MSC phenotype and functionality, and these are highly variable across laboratories. In addition, heterogeneity within MSC populations is another obstacle. Furthermore, MSCs may be isolated from several sources which adds another variable to the comparative assessment of outcomes. There is now a growing body of literature highlighting unique and distinctive properties of MSCs according to the tissue origin, and that characteristics such as donor, age, sex and underlying medical conditions may alter the therapeutic effect of MSCs. These variables must be taken into consideration when developing a cell therapy product. Having an optimal scale-up strategy for MSC manufacturing is critical for ensuring product quality while minimizing costs and time of production, as well as avoiding potential risks. Ideally, optimal scale-up strategies must be carefully considered and identified during the early stages of development, as making changes later in the bioprocess workflow will require re-optimization and validation, which may have a significant long-term impact on the cost of the therapy. This article provides a summary of important cell culture processing variables to consider in the scale-up of MSC manufacturing as well as giving a comprehensive review of tissue of origin-specific biological characteristics of MSCs and their use in current clinical trials in a range of renal pathologies.
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Affiliation(s)
| | | | - Timothy O'Brien
- Regenerative Medicine Institute (REMEDI), CÚRAM, Biomedical Science Building, National University of Ireland, Galway, Ireland
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30
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Maanaoui M, Kerr-Conte J. Pushing the boundaries of organs before it's too late: pre-emptive regeneration. Transpl Int 2021; 34:1761-1769. [PMID: 34532871 DOI: 10.1111/tri.13969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 11/28/2022]
Abstract
Solid organ transplantation is marked by accelerated aging and inexorable fibrosis. It is crucial to promote strategies to attenuate, or to reverse, damage before organ failure. Hence, the objective of this article is to provide insight into strategies, which aim to regenerate or rejuvenate the transplanted organs. Cell therapy with mesenchymal stromal cells is currently under investigation because of their antifibrotic properties. Their ability to promote mitochondrial biogenesis, and to transfer mitochondria to wounded cells, is another approach to boost the organ regeneration. Other teams have investigated bioengineered organs, which consists of decellularization of the damaged organ followed by recellularization. Lastly, the development of CAR-T cell-based technologies may revolutionize the field of transplantation, as recent preclinical studies showed that CAR-T cells could efficiently clear senescent cells from an organ and reverse fibrosis. Ultimately, these cutting-edge strategies may bring the holy grail of a pre-emptive regenerated organ closer to reality.
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Affiliation(s)
- Mehdi Maanaoui
- Department of Nephrology, CHU Lille, Lille, France.,Inserm, CHU Lille, Institut Pasteur Lille, U1190 - EGID, Univ. Lille, Lille, France
| | - Julie Kerr-Conte
- Inserm, CHU Lille, Institut Pasteur Lille, U1190 - EGID, Univ. Lille, Lille, France
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Zhang L, Lai X, Guo Y, Ma J, Fang J, Li G, Xu L, Yin W, Chen Z. Autologous bone marrow-derived mesenchymal stem cells for interstitial fibrosis and tubular atrophy: a pilot study. Ren Fail 2021; 43:1266-1275. [PMID: 34493167 PMCID: PMC8425735 DOI: 10.1080/0886022x.2021.1968432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs)-based therapy has shown promising results for renal injury. In this study, the efficacy and safety of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in treating nonspecific interstitial fibrosis and tubular atrophy (IFTA) were evaluated. Methods From March 2011 to January 2013, 11 renal transplanted patients with IFTA were recruited. At baseline, patients were given one intra-arterial infusion of BM-MSCs; 7 days and 1 month later, another two intravenous infusions of cells were followed. Serum creatinine, creatinine clearance rate, and serum cystatin-C at baseline and 7 days, 1 month, 3 months, 6 months, and 12 months after the intra-arterial infusion of BM-MSCs were used to assess renal function. At baseline and 6 months, histological examination based on hematoxylin-eosin, Masson’s trichrome and periodic acid-Schiff staining and immunohistochemistry for transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) was performed. Adverse events were recorded to evaluate the safety of BM-MSCs treatment. Results At 12 months, the renal function of 6 patients (54.5%) was improved, 3 (27.3%) were stable and 2 (18.2%) were worsened. At 6 months, the mean IFTA scores of all participators were similar with the baseline (1.73 ± 0.41 vs.1.50 ± 0.0.77, p = 0.242); however, it was significantly decreased when only 6 patients with improved renal function were analyzed (1.67 ± 0.41 vs. 1.08 ± 0.20, p = 0.013). Besides, decreased expression of TGF-β1 and CTGF were also observed at 6 months. During 1 year follow-up period, only two minor complications including infection and allergy were observed. Conclusion Our results demonstrated that autologous BM-MSCs are safe and beneficial for IFTA patients. Abbreviations: MSCs: mesenchymal stem cells; BM-MSCs: marrow-derived mesenchymal stem cells; IFTA: interstitial fibrosis and tubular atrophy; CAN: chronic allograft nephropathy; CNIs: calcineurin inhibitors; Scr: serum creatinine; CCr: creatinine clearance rate; Cys-C: cystatin-C; TGF-β1: transforming growth factor β1; CTGF: connective tissue growth factor
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Affiliation(s)
- Lei Zhang
- Department of Organ Transplantation, The Second Affiliated Hospital of Guangzhou Medical University/The Second Clinical Medicine School of Guangzhou Medical University, Guangzhou, China
| | - Xingqiang Lai
- Department of Organ Transplantation, The Second Affiliated Hospital of Guangzhou Medical University/The Second Clinical Medicine School of Guangzhou Medical University, Guangzhou, China
| | - Yuhe Guo
- Department of Organ Transplantation, The Second Affiliated Hospital of Guangzhou Medical University/The Second Clinical Medicine School of Guangzhou Medical University, Guangzhou, China
| | - Junjie Ma
- Department of Organ Transplantation, The Second Affiliated Hospital of Guangzhou Medical University/The Second Clinical Medicine School of Guangzhou Medical University, Guangzhou, China
| | - Jiali Fang
- Department of Organ Transplantation, The Second Affiliated Hospital of Guangzhou Medical University/The Second Clinical Medicine School of Guangzhou Medical University, Guangzhou, China
| | - Guanghui Li
- Department of Organ Transplantation, The Second Affiliated Hospital of Guangzhou Medical University/The Second Clinical Medicine School of Guangzhou Medical University, Guangzhou, China
| | - Lu Xu
- Department of Organ Transplantation, The Second Affiliated Hospital of Guangzhou Medical University/The Second Clinical Medicine School of Guangzhou Medical University, Guangzhou, China
| | - Wei Yin
- Department of Organ Transplantation, The Second Affiliated Hospital of Guangzhou Medical University/The Second Clinical Medicine School of Guangzhou Medical University, Guangzhou, China
| | - Zheng Chen
- Department of Organ Transplantation, The Second Affiliated Hospital of Guangzhou Medical University/The Second Clinical Medicine School of Guangzhou Medical University, Guangzhou, China
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Preconditioned Mesenchymal Stromal Cells to Improve Allotransplantation Outcome. Cells 2021; 10:cells10092325. [PMID: 34571974 PMCID: PMC8469056 DOI: 10.3390/cells10092325] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are tissue-derived progenitor cells with immunomodulatory as well as multilineage differentiation capacities, and have been widely applied as cellular therapeutics in different disease systems in both preclinical models and clinical studies. Although many studies have applied MSCs in different types of allotransplantation, the efficacy varies. It has been demonstrated that preconditioning MSCs prior to in vivo administration may enhance their efficacy. In the field of organ/tissue allotransplantation, many recent studies have shown that preconditioning of MSCs with (1) pretreatment with bioactive factors or reagents such as cytokines, or (2) specific gene transfection, could prolong allotransplant survival and improve allotransplant function. Herein, we review these preconditioning strategies and discuss potential directions for further improvement.
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Reinders MEJ, Groeneweg KE, Hendriks SH, Bank JR, Dreyer GJ, de Vries APJ, van Pel M, Roelofs H, Huurman VAL, Meij P, Moes DJAR, Fibbe WE, Claas FHJ, Roelen DL, van Kooten C, Kers J, Heidt S, Rabelink TJ, de Fijter JW. Autologous bone marrow-derived mesenchymal stromal cell therapy with early tacrolimus withdrawal: The randomized prospective, single-center, open-label TRITON study. Am J Transplant 2021; 21:3055-3065. [PMID: 33565206 PMCID: PMC8518640 DOI: 10.1111/ajt.16528] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 02/01/2021] [Accepted: 02/01/2021] [Indexed: 01/25/2023]
Abstract
After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single-center, open-label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation.
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Affiliation(s)
- Marlies E. J. Reinders
- Department of Internal Medicine (Nephrology) and Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Koen E. Groeneweg
- Department of Internal Medicine (Nephrology) and Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Sanne H. Hendriks
- Department of ImmunologyLeiden University Medical CenterLeidenthe Netherlands
| | - Jonna R. Bank
- Department of Internal Medicine (Nephrology) and Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Geertje J. Dreyer
- Department of Internal Medicine (Nephrology) and Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Aiko P. J. de Vries
- Department of Internal Medicine (Nephrology) and Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Melissa van Pel
- Department of ImmunologyLeiden University Medical CenterLeidenthe Netherlands,NECSTGENLeidenthe Netherlands
| | - Helene Roelofs
- Department of ImmunologyLeiden University Medical CenterLeidenthe Netherlands
| | - Volkert A. L. Huurman
- Department of Transplant Surgery and Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Paula Meij
- Department of Clinical Pharmacy and ToxicologyLeiden University Medical CenterLeidenthe Netherlands
| | - Dirk J. A. R. Moes
- Department of Clinical Pharmacy and ToxicologyLeiden University Medical CenterLeidenthe Netherlands
| | - Willem E. Fibbe
- Department of ImmunologyLeiden University Medical CenterLeidenthe Netherlands
| | - Frans H. J. Claas
- Department of ImmunologyLeiden University Medical CenterLeidenthe Netherlands
| | - Dave L. Roelen
- Department of ImmunologyLeiden University Medical CenterLeidenthe Netherlands
| | - Cees van Kooten
- Department of Internal Medicine (Nephrology) and Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Jesper Kers
- Department of PathologyLeiden University Medical CenterLeidenthe Netherlands,Department of PathologyAmsterdam UMCUniversity of AmsterdamAmsterdamthe Netherlands,Van ‘t Hoff Institute for Molecular Sciences (HIMS)University of AmsterdamAmsterdamthe Netherlands
| | - Sebastiaan Heidt
- Department of ImmunologyLeiden University Medical CenterLeidenthe Netherlands
| | - Ton J. Rabelink
- Department of Internal Medicine (Nephrology) and Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Johan W. de Fijter
- Department of Internal Medicine (Nephrology) and Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
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34
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Shaw BI, Ord JR, Nobuhara C, Luo X. Cellular Therapies in Solid Organ Allotransplantation: Promise and Pitfalls. Front Immunol 2021; 12:714723. [PMID: 34526991 PMCID: PMC8435835 DOI: 10.3389/fimmu.2021.714723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/04/2021] [Indexed: 12/30/2022] Open
Abstract
Donor specific transfusions have been the basis of tolerance inducing protocols since Peter Medawar showed that it was experimentally feasible in the 1950s. Though trials of cellular therapies have become increasingly common in solid organ transplantation, they have not become standard practice. Additionally, whereas some protocols have focused on cellular therapies as a method for donor antigen delivery-thought to promote tolerance in and of itself in the correct immunologic context-other approaches have alternatively focused on the intrinsic immunosuppressive properties of the certain cell types with less emphasis on their origin, including mesenchymal stem cells, regulatory T cells, and regulatory dendritic cells. Regardless of intent, all cellular therapies must contend with the potential that introducing donor antigen in a new context will lead to sensitization. In this review, we focus on the variety of cellular therapies that have been applied in human trials and non-human primate models, describe their efficacy, highlight data regarding their potential for sensitization, and discuss opportunities for cellular therapies within our current understanding of the immune landscape.
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Affiliation(s)
- Brian I. Shaw
- Department of Surgery, Duke University, Durham, NC, United States
| | - Jeffrey R. Ord
- School of Medicine, Duke University, Durham, NC, United States
| | - Chloe Nobuhara
- School of Medicine, Duke University, Durham, NC, United States
| | - Xunrong Luo
- Department of Medicine, Division of Nephrology, Duke University, Durham, NC, United States
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35
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Casiraghi F, Perico N, Podestà MA, Todeschini M, Zambelli M, Colledan M, Camagni S, Fagiuoli S, Pinna AD, Cescon M, Bertuzzo V, Maroni L, Introna M, Capelli C, Golay JT, Buzzi M, Mister M, Ordonez PYR, Breno M, Mele C, Villa A, Remuzzi G. Third-party bone marrow-derived mesenchymal stromal cell infusion before liver transplantation: A randomized controlled trial. Am J Transplant 2021; 21:2795-2809. [PMID: 33370477 DOI: 10.1111/ajt.16468] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/24/2020] [Accepted: 12/21/2020] [Indexed: 01/25/2023]
Abstract
Mesenchymal stromal cells (MSC) have emerged as a promising therapy to minimize the immunosuppressive regimen or induce tolerance in solid organ transplantation. In this randomized open-label phase Ib/IIa clinical trial, 20 liver transplant patients were randomly allocated (1:1) to receive a single pretransplant intravenous infusion of third-party bone marrow-derived MSC or standard of care alone. The primary endpoint was the safety profile of MSC administration during the 1-year follow-up. In all, 19 patients completed the study, and none of those who received MSC experienced infusion-related complications. The incidence of serious and non-serious adverse events was similar in the two groups. Circulating Treg/memory Treg and tolerant NK subset of CD56bright NK cells increased slightly over baseline, albeit not to a statistically significant extent, in MSC-treated patients but not in the control group. Graft function and survival, as well as histologic parameters and intragraft expression of tolerance-associated transcripts in 1-year protocol biopsies were similar in the two groups. In conclusion, pretransplant MSC infusion in liver transplant recipients was safe and induced mild positive changes in immunoregulatory T and NK cells in the peripheral blood. This study opens the way for a trial on possible tolerogenic efficacy of MSC in liver transplantation. ClinicalTrials.gov identifier: NCT02260375.
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Affiliation(s)
- Federica Casiraghi
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Norberto Perico
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Manuel A Podestà
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.,Renal Division, ASST Santi Paolo e Carlo, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Marta Todeschini
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Marco Zambelli
- Department of Organ Failure and Transplantation, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Michele Colledan
- Department of Organ Failure and Transplantation, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Stefania Camagni
- Department of Organ Failure and Transplantation, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Stefano Fagiuoli
- Gastroenterology, Hepatology and Transplantation, Department of Medicine, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Antonio D Pinna
- General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria-Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Matteo Cescon
- General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria-Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Valentina Bertuzzo
- General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria-Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Lorenzo Maroni
- General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria-Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Martino Introna
- G. Lanzani Laboratory of Cell Therapy, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Chiara Capelli
- G. Lanzani Laboratory of Cell Therapy, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Josee T Golay
- G. Lanzani Laboratory of Cell Therapy, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Marina Buzzi
- Emilia Romagna Cord Blood Bank, Immunohematology and Transfusion Medicine, Azienda Ospedaliero-Universitaria-Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - Marilena Mister
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Pamela Y R Ordonez
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Matteo Breno
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Caterina Mele
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Alessandro Villa
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Wong CY. Current advances of stem cell-based therapy for kidney diseases. World J Stem Cells 2021; 13:914-933. [PMID: 34367484 PMCID: PMC8316868 DOI: 10.4252/wjsc.v13.i7.914] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/10/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
Kidney diseases are a prevalent health problem around the world. Multidrug therapy used in the current routine treatment for kidney diseases can only delay disease progression. None of these drugs or treatments can reverse the progression to an end-stage of the disease. Therefore, it is crucial to explore novel therapeutics to improve patients’ quality of life and possibly cure, reverse, or alleviate the kidney disease. Stem cells have promising potentials as a form of regenerative medicine for kidney diseases due to their unlimited replication and their ability to differentiate into kidney cells in vitro. Mounting evidences from the administration of stem cells in an experimental kidney disease model suggested that stem cell-based therapy has therapeutic or renoprotective effects to attenuate kidney damage while improving the function and structure of both glomerular and tubular compartments. This review summarises the current stem cell-based therapeutic approaches to treat kidney diseases, including the various cell sources, animal models or in vitro studies. The challenges of progressing from proof-of-principle in the laboratory to widespread clinical application and the human clinical trial outcomes reported to date are also highlighted. The success of cell-based therapy could widen the scope of regenerative medicine in the future.
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Affiliation(s)
- Chee-Yin Wong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang 43000, Selangor, Malaysia
- Research Department, Cytopeutics, Cyberjaya 63000, Selangor, Malaysia
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37
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Večerić-Haler Ž, Kojc N, Sever M, Zver S, Švajger U, Poženel P, Hartman K, Urdih T, Mlinšek G, Oblak M, Aleš Rigler A, Ihan A, Buturović Ponikvar J, Halloran PP, Arnol M. Case Report: Capillary Leak Syndrome With Kidney Transplant Failure Following Autologous Mesenchymal Stem Cell Therapy. Front Med (Lausanne) 2021; 8:708744. [PMID: 34368198 PMCID: PMC8334176 DOI: 10.3389/fmed.2021.708744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have attracted great interest in the field of kidney transplantation due to their immunomodulatory and reparative properties. In registered clinical trials, MSCs have been used before, at the time of, or early after transplantation and have been reported to be well-tolerated with no serious safety concerns. No results are available on the use of MSCs in the late post-transplant period. Here, we present a case report of a severe systemic complication mimicking capillary leak syndrome with ultimate kidney transplant failure after autologous transplantation of MSCs used as rescue treatment of late antibody-mediated kidney allograft rejection.
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Affiliation(s)
- Željka Večerić-Haler
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nika Kojc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Matjaž Sever
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.,Department of Haematology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Samo Zver
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.,Department of Haematology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Urban Švajger
- Division for Cells and Tissue, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
| | - Primož Poženel
- Division for Cells and Tissue, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
| | - Katrina Hartman
- Division for Cells and Tissue, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
| | - Tereza Urdih
- Department of Haematology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Gregor Mlinšek
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Manca Oblak
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Andreja Aleš Rigler
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Alojz Ihan
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Jadranka Buturović Ponikvar
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Philip P Halloran
- Division of Nephrology and Transplant Immunology, University of Alberta, Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada
| | - Miha Arnol
- Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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38
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Wei Y, Chen X, Zhang H, Su Q, Peng Y, Fu Q, Li J, Gao Y, Li X, Yang S, Ye Q, Huang H, Deng R, Li G, Xu B, Wu C, Wang J, Zhang X, Su X, Liu L, Xiang AP, Wang C. Efficacy and Safety of Bone Marrow-Derived Mesenchymal Stem Cells for Chronic Antibody-Mediated Rejection After Kidney Transplantation- A Single-Arm, Two-Dosing-Regimen, Phase I/II Study. Front Immunol 2021; 12:662441. [PMID: 34248942 PMCID: PMC8267917 DOI: 10.3389/fimmu.2021.662441] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022] Open
Abstract
Objective To investigate the efficacy and safety of bone marrow-derived mesenchymal stem cells (BM-MSCs) on chronic active antibody-mediated rejection (cABMR) in the kidney allograft. Methods Kidney recipients with biopsy-proven cABMR were treated with allogeneic third-party BM-MSCs in this open-label, single-arm, single-center, two-dosing-regimen phase I/II clinical trial. In Regimen 1 (n=8), BM-MSCs were administered intravenously at a dose of 1.0×106 cells/kg monthly for four consecutive months, while in Regimen 2 (n=15), the BM-MSCs dose was 1.0×106 cells/kg weekly during four consecutive weeks. The primary endpoints were the absolute change of estimated glomerular filtration rate (eGFR) from baseline (delta eGFR) and the incidence of adverse events associated with BM-MSCs administration 24 months after the treatment. Contemporaneous cABMR patients who did not receive BM-MSCs were retrospectively analyzed as the control group (n =30). Results Twenty-three recipients with cABMR received BM-MSCs. The median delta eGFR of the total BM-MSCs treated patients was -4.3 ml/min per 1.73m2 (interquartile range, IQR -11.2 to 1.2) 2 years after BM-MSCs treatment (P=0.0233). The median delta maximum donor-specific antibody (maxDSA) was -4310 (IQR -9187 to 1129) at 2 years (P=0.0040). The median delta eGFR of the control group was -12.7 ml/min per 1.73 m2 (IQR -22.2 to -3.5) 2 years after the diagnosis, which was greater than that of the BM-MSCs treated group (P=0.0342). The incidence of hepatic enzyme elevation, BK polyomaviruses (BKV) infection, cytomegalovirus (CMV) infection was 17.4%, 17.4%, 8.7%, respectively. There was no fever, anaphylaxis, phlebitis or venous thrombosis, cardiovascular complications, or malignancy after BM-MSCs administration. Flow cytometry analysis showed a significant decreasing trend of CD27-IgD- double negative B cells subsets and trend towards the increase of CD3+CD4+PD-1+/lymphocyte population after MSCs therapy. Multiplex analysis found TNF-α, CXCL10, CCL4, CCL11 and RANTES decreased after MSCs treatment. Conclusion Kidney allograft recipients with cABMR are tolerable to BM-MSCs. Immunosuppressive drugs combined with intravenous BM-MSCs can delay the deterioration of allograft function, probably by decreasing DSA level and reducing DSA-induced injury. The underlying mechanism may involve immunomodulatory effect of MSCs on peripheral B and T cells subsets.
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Affiliation(s)
- Yongcheng Wei
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoyong Chen
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Huanxi Zhang
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qun Su
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanwen Peng
- The Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qian Fu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jun Li
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yifang Gao
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xirui Li
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shicong Yang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qianyu Ye
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huiting Huang
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ronghai Deng
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Gang Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Bowen Xu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chenglin Wu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiali Wang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoran Zhang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Xiaojun Su
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Longshan Liu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Changxi Wang
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Luo Y, Guo J, Zhang P, Cheuk YC, Jiang Y, Wang J, Xu S, Rong R. Mesenchymal Stem Cell Protects Injured Renal Tubular Epithelial Cells by Regulating mTOR-Mediated Th17/Treg Axis. Front Immunol 2021; 12:684197. [PMID: 34122446 PMCID: PMC8194268 DOI: 10.3389/fimmu.2021.684197] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/10/2021] [Indexed: 12/20/2022] Open
Abstract
The increase in T helper 17 cell (Th17)-mediated pro-inflammatory response and decrease in regulatory T cell (Treg)-mediated anti-inflammatory effect aggravate renal tubular epithelial cell (RTEC) injury. However, increasing evidence indicated that mesenchymal stem cell (MSC) possessed the ability to control the imbalance between Th17 and Treg. Given that Th17 and Treg are derived from a common CD4+ T cell precursor, we summarize the current knowledge of MSC-mediated inhibition of the mammalian target of rapamycin (mTOR), which is a master regulator of CD4+ T cell polarization. During CD4+ T cell differentiation, mTOR signaling mediates Th17 and Treg differentiation via hypoxia-inducible factor-1α (HIF-1α)-dependent metabolic regulation and signaling pathway, as well as mTOR-mediated phosphorylation of signal transducer and activator of transcription (STAT) 3 and 5. Through interfering with mTOR signaling, MSC restrains CD4+ T cell differentiation into Th17, but in turn promotes Treg generation. Thus, this review indicates that MSC-mediated Th17-to-Treg polarization is expected to act as new immunotherapy for kidney injury.
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Affiliation(s)
- Yongsheng Luo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jingjing Guo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Pingbao Zhang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yin Celeste Cheuk
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yamei Jiang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jiyan Wang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.,Shanghai Medical College, Fudan University, Shanghai, China
| | - Shihao Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
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40
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Wang LT, Liu KJ, Sytwu HK, Yen ML, Yen BL. Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells. Stem Cells Transl Med 2021; 10:1288-1303. [PMID: 34008922 PMCID: PMC8380447 DOI: 10.1002/sctm.21-0021] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID‐19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off‐the‐shelf products. In addition, new products such as cell‐free exosomes and human pluripotent stem cell (hPSC)‐derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications—including graft‐vs‐host‐disease, strongly Th17‐mediated autoimmune diseases, and osteoarthritis—which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.
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Affiliation(s)
- Li-Tzu Wang
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - Ko-Jiunn Liu
- National Institute of Cancer Research, National Health Research Institutes (NHRI), Tainan, Taiwan, Republic of China
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases & Vaccinology, NHRI, Zhunan, Taiwan, Republic of China.,Department & Graduate Institute of Microbiology & Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Men-Luh Yen
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, NHRI, Zhunan, Taiwan, Republic of China
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41
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Mesenchymal stromal cells for corneal transplantation: Literature review and suggestions for successful clinical trials. Ocul Surf 2021; 20:185-194. [PMID: 33607323 PMCID: PMC9878990 DOI: 10.1016/j.jtos.2021.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 01/28/2023]
Abstract
Corneal transplantation is a routine procedure for patients with corneal blindness. Despite the streamlining of surgical techniques and deeper understanding of the cellular and molecular pathways mediating rejection, corticosteroids are still the main immunosuppressive regimen in corneal transplantation, and the 15-year survival of corneal transplants remains as low as 50%, which is poorer than that for most solid organ transplants. Recently, mesenchymal stromal cells (MSCs) with unique regenerative and immune-modulating properties have emerged as a promising cell therapy to promote transplant tolerance, minimize the use of immunosuppressants, and prevent chronic rejection. Here, we review the literature on preclinical studies of MSCs for corneal transplantation and summarize the key findings from clinical trials with MSCs in solid organ transplantation. Finally, we highlight current issues and challenges regarding MSC therapies and suggest strategies for safe and effective MSC-based therapies in clinical transplantation.
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42
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Stark HL, Wang HC, Kuburic J, Alzhrani A, Hester J, Issa F. Immune Monitoring for Advanced Cell Therapy Trials in Transplantation: Which Assays and When? Front Immunol 2021; 12:664244. [PMID: 33841448 PMCID: PMC8027493 DOI: 10.3389/fimmu.2021.664244] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 03/09/2021] [Indexed: 12/29/2022] Open
Abstract
A number of immune regulatory cellular therapies, including regulatory T cells and mesenchymal stromal cells, have emerged as novel alternative therapies for the control of transplant alloresponses. Clinical studies have demonstrated their feasibility and safety, however developing our understanding of the impact of cellular therapeutics in vivo requires advanced immune monitoring strategies. To accurately monitor the immune response, a combination of complementary methods is required to measure the cellular and molecular phenotype as well as the function of cells involved. In this review we focus on the current immune monitoring strategies and discuss which methods may be utilized in the future.
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Affiliation(s)
- Helen L Stark
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Hayson C Wang
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.,Division of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jasmina Kuburic
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Alaa Alzhrani
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Joanna Hester
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Fadi Issa
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
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43
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Zhao L, Hu C, Han F, Chen D, Cheng J, Wu J, Peng W, Chen J. Induction therapy with mesenchymal stromal cells in kidney transplantation: a meta-analysis. Stem Cell Res Ther 2021; 12:158. [PMID: 33648596 PMCID: PMC7923637 DOI: 10.1186/s13287-021-02219-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 02/09/2021] [Indexed: 12/22/2022] Open
Abstract
Objective The aim of this meta-analysis was to evaluate the therapeutic effects of mesenchymal stromal cells (MSCs) versus traditional regimens for induction therapy in kidney transplantation (KT), especially the safety of MSC infusion, practicability of MSCs as induction therapy agents, and posttransplant complications. Methods PubMed, Embase, EBSCO, Ovid, and the Cochrane Library were searched for prospective clinical trials that compared MSCs with traditional regimens for induction therapy in KT. Results Four trials were included, including a total of 197 patients. The pooled results revealed that MSC therapy had a lower 1-year infection rate than did the traditional therapies (RR = 0.65, 95% CI: 0.46–0.9, P = 0.01). There were no significant differences between the two protocols regarding the 1-year acute rejection (AR) rate (RR = 0.77, 95% CI: 0.41–1.45, P = 0.42), 1-year graft survival rate (RR = 0.99, 95% CI: 0.95–1.03, P = 0.74), delayed graft function (DGF) rate (RR = 0.54, 95% CI: 0.21–1.38, P = 0.2) and renal graft function at 1 month (MD = −1.56, 95% CI: − 14.2–11.08, p = 0.81), 3 months (MD = 0.15, 95% CI: − 5.63–5.93, p = 0.96), 6 months (MD = − 1.95, 95% CI: − 9.87–5.97, p = 0.63), and 12 months (MD = − 1.13, 95% CI: − 7.16–4.89, p = 0.71) postsurgery. Subgroup analysis demonstrated that the 1-year AR rate, 1-year graft survival rate, DGF rate, and renal graft function at 12 months postsurgery did not significantly differ between the low-dose calcineurin inhibitor (CNI) group and the standard-dose CNI group, indicating the potential benefits of successful CNI sparing in combination with MSC treatment. Moreover, when MSCs were applied as an alternative therapy rather than an additional therapy or allogeneic MSCs were utilized instead of autologous MSCs, all of the outcomes mentioned above were comparable. Conclusion Induction therapy with MSCs is safe and has similar immune response modulation effects to those of traditional regimens in the short term in KT recipients. However, regarding the long-term effects, as suggested by the 1-year infection rate and the potential of CNI sparing, MSC therapy has significant advantages. However, these advantages should be further verified in more well-designed, multicenter randomized controlled trials (RCTs) with large sample sizes and long follow-up periods. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02219-7.
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Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,Institute of Nephrology, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Fei Han
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Dajin Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Jun Cheng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Jianyong Wu
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Wenhan Peng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
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Lohmann S, Eijken M, Møldrup U, Møller BK, Hunter J, Moers C, Leuvenink H, Ploeg RJ, Clahsen-van Groningen MC, Hoogduijn M, Baan CC, Keller AK, Jespersen B. Ex Vivo Administration of Mesenchymal Stromal Cells in Kidney Grafts Against Ischemia-reperfusion Injury-Effective Delivery Without Kidney Function Improvement Posttransplant. Transplantation 2021; 105:517-528. [PMID: 32956281 DOI: 10.1097/tp.0000000000003429] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Mesenchymal stromal cell (MSC) therapy may improve renal function after ischemia-reperfusion injury in transplantation. Ex vivo renal intraarterial administration is a targeted delivery method, avoiding the lung vasculature, a known barrier for cellular therapies. In a randomized and blinded study, we tested the feasibility and effectiveness of MSC therapy in a donation after circulatory death autotransplantation model to improve posttransplant kidney function, using an ex vivo MSC delivery method similar to the clinical standard procedure of pretransplant cold graft flush. METHODS Kidneys exposed to 75 minutes of warm ischemia and 16 hours of static cold storage were intraarterially infused ex vivo with 10 million male porcine MSCs (Tx-MSC, n = 8) or vehicle (Tx-control, n = 8). Afterwards, the kidneys were autotransplanted after contralateral nephrectomy. Biopsies an hour after reperfusion confirmed the presence of MSCs in the renal cortex. Animals were observed for 14 days. RESULTS Postoperatively, peak plasma creatinine was 1230 and 1274 µmol/L (Tx-controls versus Tx-MSC, P = 0.69). During follow-up, no significant differences over time were detected between groups regarding plasma creatinine, plasma neutrophil gelatinase-associated lipocalin, or urine neutrophil gelatinase-associated lipocalin/creatinine ratio. At day 14, measured glomerular filtration rates were 40 and 44 mL/min, P = 0.66. Renal collagen content and fibrosis-related mRNA expression were increased in both groups but without significant differences between the groups. CONCLUSIONS We demonstrated intraarterial MSC infusion to transplant kidneys as a safe and effective method to deliver MSCs to the graft. However, we could not detect any positive effects of this cell treatment within 14 days of observation.
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Affiliation(s)
- Stine Lohmann
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Marco Eijken
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - Ulla Møldrup
- Department of Urology, Aarhus University Hospital, Aarhus, Denmark
| | - Bjarne K Møller
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - James Hunter
- Nuffield Department of Surgical Sciences, Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Cyril Moers
- Department of Surgery-Organ Donation and Transplantation, University of Medical Center Groningen, Groningen, the Netherlands
| | - Henri Leuvenink
- Department of Surgery-Organ Donation and Transplantation, University of Medical Center Groningen, Groningen, the Netherlands
| | - Rutger J Ploeg
- Nuffield Department of Surgical Sciences, Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | | | - Martin Hoogduijn
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Carla C Baan
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Anna Krarup Keller
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Urology, Aarhus University Hospital, Aarhus, Denmark
| | - Bente Jespersen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
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45
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Johnstone BH, Messner F, Brandacher G, Woods EJ. A Large-Scale Bank of Organ Donor Bone Marrow and Matched Mesenchymal Stem Cells for Promoting Immunomodulation and Transplant Tolerance. Front Immunol 2021; 12:622604. [PMID: 33732244 PMCID: PMC7959805 DOI: 10.3389/fimmu.2021.622604] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Induction of immune tolerance for solid organ and vascular composite allografts is the Holy Grail for transplantation medicine. This would obviate the need for life-long immunosuppression which is associated with serious adverse outcomes, such as infections, cancers, and renal failure. Currently the most promising means of tolerance induction is through establishing a mixed chimeric state by transplantation of donor hematopoietic stem cells; however, with the exception of living donor renal transplantation, the mixed chimerism approach has not achieved durable immune tolerance on a large scale in preclinical or clinical trials with other solid organs or vascular composite allotransplants (VCA). Ossium Health has established a bank of cryopreserved bone marrow (BM), termed "hematopoietic progenitor cell (HPC), Marrow," recovered from deceased organ donor vertebral bodies. This new source for hematopoietic cell transplant will be a valuable resource for treating hematological malignancies as well as for inducing transplant tolerance. In addition, we have discovered and developed a large source of mesenchymal stem (stromal) cells (MSC) tightly associated with the vertebral body bone fragment byproduct of the HPC, Marrow recovery process. Thus, these vertebral bone adherent MSC (vBA-MSC) are matched to the banked BM obtained from each donor, as opposed to third-party MSC, which enhances safety and potentially efficacy. Isolation and characterization of vBA-MSC from over 30 donors has demonstrated that the cells are no different than traditional BM-MSC; however, their abundance is >1,000-fold higher than obtainable from living donor BM aspirates. Based on our own unpublished data as well as reports published by others, MSC facilitate chimerism, especially at limiting hematopoietic stem and progenitor cell (HSPC) numbers and increase safety by controlling and/or preventing graft-vs.-host-disease (GvHD). Thus, vBA-MSC have the potential to facilitate mixed chimerism, promote complementary peripheral immunomodulatory functions and increase safety of BM infusions. Both HPC, Marrow and vBA-MSC have potential use in current VCA and solid organ transplant (SOT) tolerance clinical protocols that are amenable to "delayed tolerance." Current trials with HPC, Marrow are planned with subsequent phases to include vBA-MSC for tolerance of both VCA and SOT.
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Affiliation(s)
- Brian H. Johnstone
- Ossium Health, Indianapolis, IN, United States
- Department of Biomedical Sciences, College of Osteopathic Medicine, Marian University, Indianapolis, IN, United States
| | - Franka Messner
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Erik J. Woods
- Ossium Health, Indianapolis, IN, United States
- Department of Biomedical Sciences, College of Osteopathic Medicine, Marian University, Indianapolis, IN, United States
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
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Yu Y, Valderrama AV, Han Z, Uzan G, Naserian S, Oberlin E. Human fetal liver MSCs are more effective than adult bone marrow MSCs for their immunosuppressive, immunomodulatory, and Foxp3 + T reg induction capacity. Stem Cell Res Ther 2021; 12:138. [PMID: 33597011 PMCID: PMC7888159 DOI: 10.1186/s13287-021-02176-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 01/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Nevertheless, the mechanisms underlying these observations are not well known. Direct cell contact, soluble factor production, and turning antigen-presenting cells into tolerogenic phenotypes, have been proposed to be among possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion and activity. We and others demonstrated that adult bone marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ helper and CD8+ cytotoxic T cells but also indirectly through the induction of T regs. In parallel, we demonstrated that fetal liver (FL)-MSCs demonstrates much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs. METHODS MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation, and their proliferation potential. Using different in vitro combinations, we performed co-cultures of FL- or BM-MSCs and murine CD3+CD25-T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. RESULTS We demonstrated that although both types of MSC display similar cell surface phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs. CONCLUSIONS These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.
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Affiliation(s)
- Yi Yu
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
- Beijing Institute of Stem Cells, Health & Biotech Co., Ltd, Beijing, People’s Republic of China
| | | | - Zhongchao Han
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Beijing Institute of Stem Cells, Health & Biotech Co., Ltd, Beijing, People’s Republic of China
| | - Georges Uzan
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
- Paris-Saclay University, Villejuif, France
| | - Sina Naserian
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
- Paris-Saclay University, Villejuif, France
- CellMedEx, Saint Maur des Fossés, France
| | - Estelle Oberlin
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
- Paris-Saclay University, Villejuif, France
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Clinical Trial of Allogeneic Mesenchymal Stem Cell Therapy for Chronic Active Antibody-Mediated Rejection in Kidney Transplant Recipients Unresponsive to Rituximab and Intravenous Immunoglobulin. Stem Cells Int 2021; 2021:6672644. [PMID: 33628269 PMCID: PMC7892211 DOI: 10.1155/2021/6672644] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 12/31/2020] [Accepted: 01/27/2021] [Indexed: 12/25/2022] Open
Abstract
Clinical trials of biologic agents for chronic active antibody-mediated rejection (CAMR) in kidney transplant recipients (KTRs) have been disappointing. We performed a clinical trial of mesenchymal stem cell (MSC) treatment in KTRs with CAMR unresponsive to rituximab and intravenous immunoglobulin. This study was a phase 1 clinical trial to confirm patient safety. Two patients with CAMR unresponsive to rituximab and intravenous immunoglobulin were included. Each patient received allogeneic MSCs for 4 cycles (1 × 106 cells/kg every other week) via the peripheral vein in the distal arm. We observed adverse events and renal function for 6 months after the final MSC infusion and analyzed changes in immunomodulatory parameters in the peripheral blood between the start of treatment and 3 months after the final MSC infusion. There were no serious adverse events during the study period. Renal function was stable during MSC treatment but gradually decreased between the final MSC infusion and the study endpoint (patient 1: creatinine levels ranged from 3.01 mg/dL to 7.81 mg/dL, patient 2: 2.87 mg/dL to 3.91 mg/dL). In peripheral blood sample analysis between the start of treatment and 3 months after the final MSC infusion, there were similar trends for immunomodulatory markers. Our study showed that there were no serious adverse events for six months after allogeneic MSC treatment in KTRs with CAMR refractory to rituximab and intravenous immunoglobulin, but further studies need to define the efficacy of MSC treatment in CAMR.
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48
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Podestà MA, Remuzzi G, Casiraghi F. Mesenchymal Stromal Cell Therapy in Solid Organ Transplantation. Front Immunol 2021; 11:618243. [PMID: 33643298 PMCID: PMC7902912 DOI: 10.3389/fimmu.2020.618243] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/29/2020] [Indexed: 12/29/2022] Open
Abstract
Transplantation is the gold-standard treatment for the failure of several solid organs, including the kidneys, liver, heart, lung and small bowel. The use of tailored immunosuppressive agents has improved graft and patient survival remarkably in early post-transplant stages, but long-term outcomes are frequently unsatisfactory due to the development of chronic graft rejection, which ultimately leads to transplant failure. Moreover, prolonged immunosuppression entails severe side effects that severely impact patient survival and quality of life. The achievement of tolerance, i.e., stable graft function without the need for immunosuppression, is considered the Holy Grail of the field of solid organ transplantation. However, spontaneous tolerance in solid allograft recipients is a rare and unpredictable event. Several strategies that include peri-transplant administration of non-hematopoietic immunomodulatory cells can safely and effectively induce tolerance in pre-clinical models of solid organ transplantation. Mesenchymal stromal cells (MSC), non-hematopoietic cells that can be obtained from several adult and fetal tissues, are among the most promising candidates. In this review, we will focus on current pre-clinical evidence of the immunomodulatory effect of MSC in solid organ transplantation, and discuss the available evidence of their safety and efficacy in clinical trials.
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Affiliation(s)
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Bergamo, Italy
| | - Federica Casiraghi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Bergamo, Italy
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Andres AM, Stringa P, Talayero P, Santamaria M, García-Arranz M, García Gómez-Heras S, Largo-Aramburu C, Aras-Lopez RM, Vallejo-Cremades MT, Guerra Pastrián L, Vega L, Encinas JL, Lopez-Santamaria M, Hernández-Oliveros F. Graft infusion of adipose-derived mesenchymal stromal cells to prevent rejection in experimental intestinal transplantation: A feasibility study. Clin Transplant 2021; 35:e14226. [PMID: 33465824 DOI: 10.1111/ctr.14226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/30/2020] [Accepted: 01/12/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Mesenchymal stromal cells (MSC) have been proposed as a promising complement to standard immunosuppression in solid organ transplantation because of their immunomodulatory properties. The present work addresses the role of adipose-derived MSC (Ad-MSC) in an experimental model of acute rejection in small bowel transplantation (SBT). MATERIAL/METHODS Heterotopic allogeneic SBT was performed. A single dose of 1.5x106 Ad-MSC was intra-arterially delivered just before graft reperfusion. Animals were divided into CONTROL (CTRL), CONTROL+Ad-MSC (CTRL_MSC), tacrolimus (TAC), and TAC+Ad-MSC (TAC_MSC) groups. Each Ad-MSC groups was subdivided in autologous and allogeneic third-party groups. RESULTS Rejection rate and severity were similar in MSC-treated and untreated animals. CTRL_MSC animals showed a decrease in macrophages, T-cell (CD4, CD8, and Foxp3 subsets) and B-cell counts in the graft compared with CTRL, this decrease was attenuated in TAC_MSC animals. Pro- and anti-inflammatory cytokines and some chemokines and growth factors increased in CTRL_MSC animals, especially in the allogeneic group, whereas milder changes were seen in the TAC groups. CONCLUSION Ad-MSC did not prevent rejection when administered just before reperfusion. However, they showed immunomodulatory effects that could be relevant for a longer-term outcome. Interference between tacrolimus and the MSC effects should be addressed in further studies.
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Affiliation(s)
- Ane M Andres
- Pediatric Surgery Department, La Paz University Hospital, Madrid, Spain.,Idipaz Institute, La Paz University Hospital, Madrid, Spain.,TransplantChild ERN, Idipaz Institute, La Paz University Hospital, Madrid, Spain
| | - Pablo Stringa
- Institute for Immunological and Physiopathological Studies (IIFP-CONICET-UNLP), National University of La Plata, Buenos Aires, Argentina
| | - Paloma Talayero
- Immunology Department, 12 de Octubre University Hospital, Madrid, Spain.,imas12 Research Institute, 12 de Octubre University Hospital, Madrid, Spain
| | - Monica Santamaria
- Experimental Transplant Department, Alfonso X University, Madrid, Spain
| | | | | | | | - Rosa M Aras-Lopez
- Research Institute, Idipaz Institute, La Paz University Hospital, Madrid, Spain
| | | | | | - Luz Vega
- Health Research Institute, Fundación Jimenez Diaz, Madrid, Spain
| | - Jose Luis Encinas
- Pediatric Surgery Department, La Paz University Hospital, Madrid, Spain
| | | | - Francisco Hernández-Oliveros
- TransplantChild ERN, Idipaz Institute, La Paz University Hospital, Madrid, Spain.,Health Research Institute, Fundación Jimenez Diaz, Madrid, Spain.,Pediatric Surgery Department EOC TransplantChild ERN, La Paz University Hospital, Madrid, Spain
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Hoogduijn MJ, Issa F, Casiraghi F, Reinders MEJ. Cellular therapies in organ transplantation. Transpl Int 2021; 34:233-244. [PMID: 33207013 PMCID: PMC7898347 DOI: 10.1111/tri.13789] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/15/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023]
Abstract
Cellular therapy is a promising tool for improving the outcome of organ transplantation. Various cell types with different immunoregulatory and regenerative properties may find application for specific transplant rejection or injury-related indications. The current era is crucial for the development of cellular therapies. Preclinical models have demonstrated the feasibility of efficacious cell therapy in transplantation, early clinical trials have shown safety of several of these therapies, and the first steps towards efficacy studies in humans have been made. In this review, we address the current state of the art of cellular therapies in clinical transplantation and discuss monitoring tools and endpoints for these studies.
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Affiliation(s)
- Martin J. Hoogduijn
- Nephrology and TransplantationDepartment of Internal MedicineErasmus University Medical CenterErasmus Medical CenterRotterdamThe Netherlands
| | - Fadi Issa
- Transplantation Research and Immunology GroupNuffield Department of Surgical SciencesJohn Radcliffe HospitalUniversity of OxfordOxfordUK
| | | | - Marlies E. J. Reinders
- Nephrology and TransplantationDepartment of Internal MedicineErasmus University Medical CenterErasmus Medical CenterRotterdamThe Netherlands
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