ER stress relief drives beta cell proliferation

Regenerating endogenous pancreatic beta cells is a potentially curative yet currently elusive strategy for diabetes therapy. Mimicking the microenvironment of the developing pancreas and leveraging vascular signals that support pancreatic endocrinogenesis may promote beta cell regeneration. We aimed to investigate whether recovery from experimental hypovascularization of the endocrine pancreas, achieved by modulating the transgenic production of a VEGF-A blocker in beta cells, could trigger mouse beta cell proliferation. Serendipitously, we found that transgene overexpression in beta cells induces endoplasmic reticulum (ER) stress and that subsequent relief from this stress stimulates beta cell proliferation independent of vessel recovery. Transient GFP overexpression in vivo and chemical induction of ER stress in vitro replicated this beta cell cycling response. Our findings highlight the potential side effects of ER stress due to transgene overexpression in beta cells and assert that ER stress relief serves as a potent regenerative stimulus.