Islet transplantation for the treatment of type 1 diabetes relies on the availability of appropriate pancreata and the transplantation success is challenged by poor engraftment due to the lack of vascularization and instant blood mediated inflammatory response (IBMIR). Therefore single-donor transplantation is not effective at controlling glycemia.

We used a multi-disciplinary approach to address donor scarcity, ischemia and IBMIR concurrently. We used human embryonic stem cell-derived pancreatic progenitors (PP) as a renewable source for pancreatic tissue. As vascularization strategies, we used adipose-derived microvessels (MV) which are short fragments with intact endothelium and perivascular cell coverage, or with single endothelial cells (EC). To avoid IBMIR we used the subcutaneous site for the transplantation or PP alone, or PP+MV or PP+EC. At 1-week post-transplantation, MV connected perfused with host blood and rescued hypoxia and apoptosis in the co-transplanted PP. Further, the recipients of PP+MV, reached normoglycemia 7-8 weeks post-transplantation while PP and PP+EC recipients failed to normalize blood glucose. The PP+MV grafts but not PP or PP+EC grafts responded to glucose-stimulated insulin secretion assay (GSIS) at week 7 post-transplantation. Interestingly, once the grafts were removed from the mice and placed ex vivo, the PP, PP+MV and PP+EC grafts reposed to GSIS, highlighting that without an effective vasculature in vivo graft function is jeopardized. Further, co-transplantation of human islets with MV led to successful islet engraftment and survival in the subcutis, resulting in immediate normoglycemia with subtherapeutic islet doses. Moreover, MV replenished a dense intraislet vasculature, resembling that of native islets. Therefore, MV offer an effective vascularization strategy to ensure pancreatic cell survival and function in vivo by minimally invasive subcutaneous transplantation.