Mesenchymal Stem Cells Enhance Allogeneic Islet Engraftment in Nonhuman Primates

Abstract

OBJECTIVETo test the graft-promoting effects of mesenchymal stem cells (MSCs) in a cynomolgus monkey model of islet/bone marrow transplantation.RESEARCH DESIGN AND METHODSCynomolgus MSCs were obtained from iliac crest aspirate and characterized through passage 11 for phenotype, gene expression, differentiation potential, and karyotype. Allogeneic donor MSCs were cotransplanted intraportally with islets on postoperative day (POD) 0 and intravenously with donor marrow on PODs 5 and 11. Recipients were followed for stabilization of blood glucose levels, reduction of exogenous insulin requirement (EIR), C-peptide levels, changes in peripheral blood T regulatory cells, and chimerism. Destabilization of glycemia and increases in EIR were used as signs of rejection; additional intravenous MSCs were administered to test the effect on reversal of rejection.RESULTSMSC phenotype and a normal karyotype were observed through passage 11. IL-6, IL-10, vascular endothelial growth factor, TGF-β, hepatocyte growth factor, and galectin-1 gene expression levels varied among donors. MSC treatment significantly enhanced islet engraftment and function at 1 month posttransplant (n = 8), as compared with animals that received islets without MSCs (n = 3). Additional infusions of donor or third-party MSCs resulted in reversal of rejection episodes and prolongation of islet function in two animals. Stable islet allograft function was associated with increased numbers of regulatory T-cells in peripheral blood.CONCLUSIONSMSCs may provide an important approach for enhancement of islet engraftment, thereby decreasing the numbers of islets needed to achieve insulin independence. Furthermore, MSCs may serve as a new, safe, and effective antirejection therapy.

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

“…Berman et al first reported that infusions of donor or thirdparty MSCs reversed rejection episodes and prolonged islet function, associated with increased numbers of Tregs in peripheral blood [60]. We hypothesized that iPSC-MSCs act like adult MSCs to induce Tregs.…”

Mesenchymal stem cells differentially mediate regulatory T cells and conventional effector T cells to protect fully allogeneic islet grafts in mice

“…Thus, an optimal approach would involve an improved islet transplantation protocol that would prevent graft rejection without the need for potentially dangerous long-term and non-specific immune suppression. Previous reports [21], including our own results [8], have shown that the infusion of MSCs results in a reversal of rejection episodes and a prolongation of islet function in islet-transplanted animal models, cementing the rationale for the therapeutic application of MSCs in allogeneic islet transplantation. The precise mechanisms involved in the beneficial effects of MSCs in allogeneic islet transplantation, however, require further investigation.…”

“…Our findings that MSCs preferentially inhibit the expansion of T eff cells while sparing T reg activity prompted us to analyse the therapeutic potential of MSCs in an islet-transplanted mouse model. Recently, the therapeutic effects of MSCs in islet transplantation have been described in a non-primate animal model in which MSC treatment significantly enhanced islet engraftment and resulted in a reversal of rejection episodes [21].…”

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

“…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…”

“…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).…”