PURPOSE: Islet transplantation represents a promising procedure to reverse or prevent diabetes. However, significant mass of islet graft is lost within hours of transplantation due to an acute inflammatory response. Mesenchymal stem cells (MSCs) have been shown to protect islets from inflammation and have capabilities to regenerate islet tissue in animal models. We hypothesized that the inflamed pancreas in chronic pancreatitis (CP) patients is enriched with MSCs that are programmed to mediate inflammatory protection and tissue restoration processes.

METHODS: MSCs from CP patients (n=14) having autologous islet transplantation following total pancreatectomy were isolated from pancreatic remnant tissue recovered during clinical islet isolation procedures. Pancreas-derived MSCs (PMSCs) (∼1X10 ⁶ ) were co-transplanted with isolated human islets (∼1500) into kidney capsules of nude mice with streptozotocin (STZ)-induced diabetes and islet grafts were assessed for function. PMSCs were compared with bone marrow derived MSCs (BMSCs) for capabilities to suppress islet inflammation and differentiate into insulin-producing cells.

RESULTS: PMSCs co-transplanted with a marginal dose of human islets reversed hyperglycemia and restored IPGTT profiles in diabetic mice (n=5) (Fig 1). PMSCs showed higher potency compared to BMSCs in the induction of genes including PDX-1, NeuroD1, NKx6.1, MafA, GLUT2, and insulin for beta-cell differentiation and conversion into insulin-producing cells. PMSCs also had an enhanced capacity to suppress (27.5 ± 1.2%) T-cell proliferation by a mechanism requiring expression of indoleamine-2-3-dioxygnease (IDO) (Fig 2).

CONCLUSIONS: PMSCs have a high potency to 1) suppress islet inflammation, 2) enhance islet graft function, and 3) differentiate into insulin-producing cells. Their use as adjunctive therapy in clinical islet autologous and allogeneic transplantation should be explored.

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