Cotransplantation of Mesenchymal Stem Cells With Neonatal Porcine Islets Improve Graft Function in Diabetic Mice

Abstract

Mesenchymal stem cells (MSCs) possess immunoregulatory, anti-inflammatory, and proangiogenic properties and, therefore, have the potential to improve islet engraftment and survival. We assessed the effect human bone marrow-derived MSCs have on neonatal porcine islets (NPIs) in vitro and determined islet engraftment and metabolic outcomes when cotransplanted in a mouse model. NPIs cocultured with MSCs had greater cellular insulin content and increased glucose-stimulated insulin secretion. NPIs were cotransplanted with or without MSCs in diabetic B6.129S7-Rag1/J mice. Blood glucose and weight were monitored until reversal of diabetes; mice were then given an oral glucose tolerance test. Islet grafts were assessed for the degree of vascularization and total cellular insulin content. Cotransplantation of NPIs and MSCs resulted in significantly earlier normoglycemia and vascularization, improved glucose tolerance, and increased insulin content. One experiment conducted with MSCs from a donor with an autoimmune disorder had no positive effects on transplant outcomes. Cotransplantation of human MSCs with NPIs demonstrated a beneficial metabolic effect likely as a result of earlier islet vascularization and improved islet engraftment. In addition, donor pathology of MSCs can influence the functional capacity of MSCs.

Characterization of the Effects of Mesenchymal Stromal Cells on Mouse and Human Islet Function

“…This raises the possibility of enhancing islet graft functional survival by treating the islets with MSCs before transplantation , so avoiding the logistical, safety, and regulatory concerns of codelivering MSCs in clinical islet transplantation protocols. To date, experimental studies have used a range of different MSCs and in vitro culture conditions , but the effective translation of these experimental observations into improved clinical protocols will require consensus about how best to use MSCs to support graft function. In the current study, we have investigated a number of parameters to optimize the beneficial effects of in vitro coculture of islets with MSCs.…”

“…Mesenchymal stromal cells (MSCs) offer the potential for improving the outcomes of islet transplantation by exerting anti‐inflammatory, immunosuppressant, and regenerative effects to protect the islet graft . Several studies have demonstrated that cotransplantation of MSCs with islets has beneficial effects on graft function to maintain normoglycemia in animal models of T1D . Some of these effects can be attributed to MSCs influencing the host niche to reduce inflammation , to suppress acquired immune responses , and to enhance graft revascularization .…”

Using Mesenchymal Stromal Cells in Islet Transplantation

“…Studies in rodent models of diabetes have demonstrated that cotransplanting MSCs with islets improves the outcome of islet transplantation in terms of glycemic control . These beneficial effects have been attributed to the ability of MSCs to enhance revascularization or to suppress the host immune responses to the graft .…”

“…These beneficial effects have been attributed to the ability of MSCs to enhance revascularization or to suppress the host immune responses to the graft . However, MSCs also improve transplantation outcomes of syngenic grafts , which do not provoke an immune response, and in microencapsulated islet grafts , which do not revascularize, suggesting that MSCs improve graft outomes via multiple mechanisms.…”

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

“…MSCs induce an anti‐inflammatory, immunomodulatory and proangiogenic effect through the secretion of trophic factors such as hepatocyte growth factor (HGF), transforming growth factor β (TGF‐β), vascular endothelial growth factor (VEGF) interleukin‐6 (IL‐6), interleukin‐10 (IL‐10), annexin A1, indoleamine‐2,3‐dioxygenase (IDO), and prostaglandin‐E2 (PGE2) . Our previous study demonstrates that NPI co‐transplanted with bone marrow–derived mesenchymal stem cells (BMSCs) induce the rapid graft vascularization and thereby enhances the graft function . Therefore, these cells may have the potential to stimulate rapid graft vascularization and modulate the immune microenviroment within the DL subcutaneous space and thereby enhancing the function of co‐transplanted islets.…”