Mesenchymal Stem Cells Prevent Acute Rejection and Prolong Graft Function in Pancreatic Islet Transplantation

Longoni, Biancamaria; Szilàgyi, Erzsèbet; Quaranta, Paola; Paoli, Giacomo Timoteo; Tripodi, Sergio; Urbani, Serena; Mazzanti, Benedetta; Rossi, Benedetta; Fanci, Rosa; Demontis, Gian Carlo; Marzola, Pasquina; Saccardi, Riccardo; Cintorino, Marcella; Mosca, Franco

doi:10.1089/dia.2009.0154

Cited by 70 publications

(73 citation statements)

References 53 publications

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“…Furthermore, adult MSCs inhibit Th1 and IFN-g secretion in vitro [57,58]. Using a rat model of STZ-induced diabetes, adult MSCs significantly improved glycemic control and reduced inflammatory cell infiltration in either allogeneic or syngeneic pancreatic islet transplantation [59]. In this study, iPSCMSCs + Rapa treatment effectively decreased the proportion of splenic and lymph node CD4 + and CD8 + T lymphocytes in vivo and strongly inhibited T-cell proliferation.…”

Section: Discussionmentioning

confidence: 55%

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

Cheng

Xiao-cun

et al. 2015

Stem Cells and Development

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Mesenchymal stem cell (MSC) differentiation is dramatically reduced after long-term in vitro culture, which limits their application. MSCs derived from induced pluripotent stem cells (iPSCs-MSCs) represent a novel source of MSCs. In this study, we investigated the therapeutic effect of iPSC-MSCs on diabetic mice. Streptozocin-induced diabetic mice transplanted with 400 islets alone or with 1 · 10 6 iPSC-MSCs were examined following rapamycin injection (0.1 mg/kg/day, i.p., from days 0 to 9) after transplantation. Our results showed that iPSC-MSCs combined with rapamycin significantly prolonged islet allograft survival in the diabetic mice; 50% of recipients exhibited long-term survival ( > 100 days). Histopathological analysis revealed that iPSCMSCs combined with rapamycin preserved the graft effectively, inhibited inflammatory cell infiltration, and resulted in substantial release of insulin. Flow cytometry results showed that the proportion of CD4 + and CD8 + T cells was significantly reduced, and the number of T regulatory cells increased in the spleen and lymph nodes in the iPSC-MSCs combined with the rapamycin group compared with the rapamycin-alone group. Production of the Th1 proinflammatory cytokines interleukin-2 (IL-2) and interferon-g was reduced, and secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor-b was enhanced compared with the rapamycin group, as determined using enzyme-linked immunosorbent assays. Transwell separation significantly weakened the immunosuppressive effects of iPSC-MSCs on the proliferation of Con A-treated splenic T cells, which indicated that the combined treatment exerted immunosuppressive effects through cell-cell contact and regulation of cytokine production. Taken together, these findings highlight the potential application of iPSCMSCs in islet transplantation.

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Section: Discussionmentioning

confidence: 55%

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

Cheng

Xiao-cun

et al. 2015

Stem Cells and Development

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“…In agreement with other reports on islets/BMSCs co-transplantation [67,137], our results indicated that the co-transplantation of islets with Adv-hHGF-hIL-1Ra-transduced primary BMSCs into diabetic NOD-SCID mice promoted local revascularization, improved islet viability and reversed diabetes in long term. We are the first group to report the combination strategy of Adv-based gene therapy and BMSC-based cell therapy to improve the outcome of islet transplantation.…”

Section: Discussionsupporting

confidence: 92%

“…Ding et al reported that BMSCs co-transplanted under the kidney capsule of immune competent mice protected islet grafts by inhibiting the alloreactivity of infiltrating T cells [60]. Longoni et al reported that BMSCs induced a reduction of inflammatory cytokines and improved the viability of islets infused into the portal vein of diabetic rats [67]. Li et al reported reduced Th1/Th2 ratio, Tc cells and Tm cells number and suppressed DCs maturation once BMSCs were co-transplanted with allograft islets under the kidney capsules of diabetic C57LB/6 mouse [68].…”

Section: Bmscs Prevent Graft Rejectionmentioning

confidence: 99%

Gene Therapy and Stem Cell Therapy to Improve the Outcome of Human Islet Transplantation

Wu¹

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revised all my manuscripts and gave me the courage and the skills to write and present as a non-native English speaker.I must acknowledge as well the many friends, colleagues, students, teachers, and other librarians who assisted, advised, and supported my research and writing efforts over the years. Especially, I need to express my gratitude and deep appreciation to my wife Chengcheng Liu whose understanding, wisdom, and sense of humor have supported, enlightened, and entertained me over many years. She has consistently helped me keep perspective on what is important in life and shown me how to deal with reality.

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“…Attenuation of donor reactive T cells increases the efficacy of T regs therapy in prevention of islet allograft rejection (165). Several studies have proven the immunomodulatory effects of MSCs and efficacy of these cells to preserve islets from immune attack when co-transplanted (166,167,168,169,170). Different immunosuppressive mechanisms proposed for MSCs include Th1 suppression (167), Th1 to Th2 shift (166), reduction of CD25 surface expression on responding T-cells through MMP-2 and 9 (169), marked reduction of memory T cells (166), enhancement of IL10 producing CD4…”

Section: Central Tolerance Inductionmentioning

confidence: 99%

“…C T cells (167), increase in peripheral blood T reg numbers (168), suppression of DC maturation and endocytic activity of these cells (166), as well as reduction of pro-inflammatory cytokines such as IFN-g (170). An ongoing phase 1/2 clinical trial in China has assessed the safety and efficacy of intra-portal co-transplantation of islets and MSCs (ClinicalTrials.gov, identifier: NCT00646724).…”

Section: Central Tolerance Inductionmentioning

confidence: 99%

THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away

Khosravi‐Maharlooei¹,

Hajizadeh‐Saffar²,

Tahamtani³

et al. 2015

European Journal of Endocrinology

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Over the past decades, tremendous efforts have been made to establish pancreatic islet transplantation as a standard therapy for type 1 diabetes. Recent advances in islet transplantation have resulted in steady improvements in the 5-year insulin independence rates for diabetic patients. Here we review the key challenges encountered in the islet transplantation field which include islet source limitation, sub-optimal engraftment of islets, lack of oxygen and blood supply for transplanted islets, and immune rejection of islets. Additionally, we discuss possible solutions for these challenges.

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Mesenchymal Stem Cells Prevent Acute Rejection and Prolong Graft Function in Pancreatic Islet Transplantation

Abstract: The results show that MSCs modulate the immune response through a down-regulation of pro-inflammatory cytokines, suggesting that MSCs may prevent acute rejection and improve graft function in portal vein pancreatic islet transplantation.

Cited by 70 publications

References 53 publications

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

Gene Therapy and Stem Cell Therapy to Improve the Outcome of Human Islet Transplantation

THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away

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