Immune evasive human islet-like organoids ameliorate diabetes

While stem cell-derived islets hold promise as a therapy for insulin-dependent diabetes, challenges remain in achieving this goal(1–6). Here we generate human islet-like organoids (HILOs) from induced pluripotent stem cells (iPSCs) and show that non-canonical WNT4 signaling drives the metabolic maturation necessary for robust ex vivo glucose-stimulated insulin secretion. These functionally mature HILOs contain endocrine-like cell types that, upon transplantation, rapidly re-establish glucose homeostasis in diabetic NOD-SCID mice. Overexpression of the immune checkpoint protein PD-L1 protected HILO xenografts such that they were able to restore glucose homeostasis in immune-competent diabetic mice for 50 days. Furthermore, ex vivo interferon gamma stimulation induced endogenous PD-L1 expression and restricted T cell activation and graft rejection. The generation of glucose-responsive islet-like organoids able to avoid immune detection provides a promising alternative to cadaveric and device-dependent therapies in the treatment of diabetes.