Although stem cell populations mediate regeneration of rapid turnover tissues, such as skin, blood, and gut, a stem cell reservoir has not been identified for some slower turnover tissues, such as the pancreatic islet. Despite lacking identifiable stem cells, murine pancreatic ß cell number expands in response to an increase in insulin demand. Lineage tracing shows that new ß cells are generated from proliferation of mature, differentiated ß cells; however, the mechanism by which these mature cells sense systemic insulin demand and initiate a proliferative response remains unknown. Here, we identified the ß cell unfolded protein response (UPR), which senses insulin production, as a regulator of ß cell proliferation. Using genetic and physiologic models, we determined that among the population of ß cells, those with an active UPR are more likely to proliferate. Moreover, subthreshold endoplasmic reticulum stress (ER stress) drove insulin demand–induced ß cell proliferation, through activation of ATF6. We also confirmed that the UPR regulates proliferation of human ß cells, suggesting that therapeutic UPR modulation has potential to expand ß cell mass in people at risk for diabetes. Together, this work defines a stem cell–independent model of tissue homeostasis, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand.

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