Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic β cells

Loss of functional pancreatic beta cells is a hallmark of both type 1 and 2 diabetes. Identifying the pathways that promote beta cell proliferation and/or block beta cell apoptosis is a potential strategy for diabetes therapy. The transcriptional coactivator Yes-associated protein (YAP), a major downstream effector of the Hippo signaling pathway, is a key regulator of organ size and tissue homeostasis by modulating cell proliferation and apoptosis. YAP is not expressed in mature primary human and mouse beta cells. We aimed to identify whether reexpression of a constitutively active form of YAP promotes beta cell proliferation/survival. Overexpression of YAP remarkably induced beta cell proliferation in isolated human islets, while beta cell function and functional identity genes were fully preserved. The transcription factor forkhead box M1 (FOXM1) was upregulated upon YAP overexpression and necessary for YAP-dependent beta cell proliferation. YAP overexpression protected beta cells from apoptosis triggered by multiple diabetic conditions. The small redox proteins thioredoxin-1 and thioredoxin-2 (Trx1/2) were upregulated by YAP; disruption of the Trx system revealed that Trx1/2 was required for the antiapoptotic action of YAP in insulin-producing beta cells. Our data show the robust proproliferative and antiapoptotic function of YAP in pancreatic beta cells. YAP reconstitution may represent a disease-modifying approach to restore a functional beta cell mass in diabetes.