Co‐transplantation of human adipose‐derived mesenchymal stem cells with neonatal porcine islets within a prevascularized subcutaneous space augments the xenograft function

Abstract

Background Cell transplantation has been widely recognized as a curative treatment strategy for variety of diseases including type I diabetes (T1D). Broader patient inclusion for this therapeutic option is restricted by a limited supply of healthy human islet donors and significant loss of islets immediately postintrahepatic transplant due to immune activation. Neonatal porcine islets (NPIs) are a potential ubiquitous β‐cell source for treating T1D. Mesenchymal stem cells (MSCs) have the inherent capacity to secrete immunoregulatory, anti‐inflammatory, and proangiogenic factors and, thus, have the potential to improve islet engraftment, survival, and function. Methods Herein, we assessed the effect of human adipose–derived MSCs (AdMSCs) on NPI metabolic outcomes in diabetic mice when co‐transplanted within the prevascularized subcutaneous deviceless (DL) space or kidney capsule (KC). Graft function has been evaluated by weekly blood glucose, stimulated porcine insulin, glucose tolerance, and total cellular graft insulin content. Results Compared with NPI alone, co‐transplantation of NPIs and AdMSCs resulted in significantly earlier normoglycemia (*P < .05), improved glucose tolerance (*P < .05), superior stimulated serum porcine insulin (**P < .01), and increased graft insulin content (*P < .05) in the DL site and not the KC. Conclusions Thus, our study demonstrates that co‐transplantation of human AdMSCs with NPIs is an effective tactic to augment islet xenograft function in a clinically relevant extrahepatic site.

White Adipose Tissue as a Site for Islet Transplantation

“…Regarding immunomodulation, ADMSCs support immunotolerance in the transplant site by hindering the infiltration of CD4+ and CD8+ T cells [95] and macrophages [94], as well as by promoting the production and infiltration of Tregs [96]. A recent study revealed that xenogeneic co-transplantation of human ADMSCs with neonatal porcine islets led to earlier achievement normoglycemia in diabetic mice compared with transplantation of porcine islets only [97]. These functions of ADMSCs are characterized as supportive effects for promoting the engraftment of transplanted islets.…”

<p>Multifunctional Islet Transplantation Hydrogel Encapsulating A20 High-Expressing Islets</p>

“…Mesenchymal stem cells (MSCs) are widely used to be co-transplanted with islets. [35][36][37][38][39] When co-transplanted with islets in recipients, MSCs can promote angiogenesis in situ to prevent hypoxia and to attenuate immune rejection. MSCs can suppress various immune cells such as NK cells, macrophages, neutrophils, and T cells.…”

Xenotransplantation literature update, July/August 2020

“…It has shown that dendritic cell (DC)‐based cell therapy has a potential to promote transplantation tolerance and could help to reduce/replace immunosuppressive treatments 8 . Madelon et al generated tolerogenic DCs by differentiating bone marrow (BM) cells in the presence of granulocyte‐macrophage colony‐stimulating factor and interleukin 10 (IL‐10 DC) 9 . IL‐10 DCs produced high amounts of IL‐10 and low amounts of pro‐inflammatory cytokines and induced weak T‐cell proliferation.…”