Genetic manipulation of stress pathways can protect stem-cell-derived islets from apoptosis in vitro.

The in vitro production of stem-cell-derived islets (SC-islets) has brought forth the potential of transplanting these cells to restore glycemic control in people with diabetes. Nonetheless, alloimmune and autoimmune responses remain considerable challenges for a broad clinical implementation of β-cell replacement therapies. β-cell stress has been implicated in the onset of β-cell immunogenicity and death and is likely to contribute to β-cell failure following transplantation. We show that inducing stress and/or administering cytokines causes SC-islet apoptosis, cellular dysfunction, and an increased expression of β-cell stress- and immune-interaction-related genes. We then demonstrate that manipulating some of these genes results in enhanced protection of SC-islets from apoptosis in vitro.