Extending Immune-Evasive Human Islet-Like Organoids (HILOs) Survival and Function as a Cure for T1D

Pancreatic islet transplantation offers a long-term treatment for Type 1 diabetes (T1D), however the shortage of donors and the need for immunosuppressive drugs restrict its therapeutic utility. The generation of human islet-like organoids (HILOs) that exhibit robust glucose-stimulated insulin secretion and survive in immune-competent mice was previously described. The overarching goal of this proposal was to prolong HILO graft survival and function as a long-term treatment or cure for T1D. In particular, this proposal sought to utilize fibroblast growth factor 1 (FGF1) to reduce the acute loss of transplanted HILOs due to the combination of poor vascularization of grafted organoids and the metabolic stresses imposed on the transplanted cells by the recipient’s diabetes. With respect to graft vascularization, we identified a cocktail of growth factors that effectively stimulate the growth of vessels from HILOs, as well as identified a novel approach using a monoclonal antibody. We expect that both approaches will promote the formation of blood vessels that are essential to provide oxygen and nutrients to the transplanted organoids, as well as for the removal of cellular wastes, and thereby prolong graft survival. With respect to modulating the metabolic stresses, we demonstrated that exogenous FGF1 improved glucose control in T1D mouse models. Moreover, FGF1 treatment promoted the survival and/or proliferation of the remaining pancreatic b cells. We are optimistic that these beneficial effects of FGF1 treatment will prolong the functional longevity of grafted HILOs and pave the way for immunosuppression-free β-cell replacement therapies in the clinic.