Transient ER stress cell-autonomously promotes beta cell cycling

Regenerating endogenous pancreatic ß-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 ß-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 ß-cells, could trigger mouse ß-cell proliferation. Serendipitously, we found that transgene overexpression in ß-cells induces endoplasmic reticulum (ER) stress and that subsequent relief from this stress stimulates ß-cell proliferation independent of vessel recovery. Transient GFP overexpression in vivo and transient chemical induction of ER stress in vitro replicated this ß-cell cycling response. Our findings highlight the potential side effects of ER stress due to transgene overexpression in ß-cells and assert that ER stress relief serves as a potent regenerative stimulus. Overall design: Pancreatic islets were isolated from RIP-rtTA;TetO-sFLT1 mice and subsequently dissociated. For each condition (No DOX, +DOX, and WD4D), two biological replicates were included, resulting in a total of six samples that were analyzed using scRNAseq.