The Hippo pathway terminal effector YAP modulates b-cell regeneration and diabetes

Abstract

Diabetes, characterized by chronic hyperglycemia and severe metabolic disorders, is a major public health problem worldwide. In type 1 diabetes (T1D), β-cell loss is caused by immune- mediated destruction, whereas in type 2 diabetes (T2D), β-cell loss is initially caused by an increase in β-cell insulin requirements. Pancreatic β-cell apoptosis and loss of β-cell mass is a common feature of both T1D and T2D. Identifying the key regulatory mechanisms and active signaling pathways involved in β-cell failure is required for future strategies to prevent β-cell destruction and promote β-cell regeneration in diabetes. I show in this thesis that a critical downstream component of the Hippo pathway, the co-transcription factor Yes-associated protein (YAP), has a dual role in T1D. YAP potently promoted β-cell proliferation, protected from β-cell apoptosis and restored β-cell mass. Conversely, in the presence of enteroviruses, YAP was pro-apoptotic; it potentiated enterovirus induced inflammation and cell death. In the first part of my dissertation I investigated the potential role of YAP induction in β-cells in vivo in mice with β-cell specific YAP overexpression. In this study, I found that YAP overexpression induced robust proliferation in both male and female mice, and subsequently increased β-cell mass. Overexpression of YAP in a model of T1D, namely through specific destruction of β-cells by streptozotocin (STZ) prevented diabetes induction. In both control and STZ-injected mice, YAP promoted β-cell mass, proliferation and protected β-cells from apoptosis. In the STZ mice, YAP’s protective effect was mainly based on its negative transcriptional and translational effect on the expression of the glucose transporter GLUT2, a critical component of glucose metabolism and insulin secretion in β-cells. YAP, the downstream transcriptional effector of the Hippo pathway, acts through its major transcription factor TEAD. In the second part of my thesis, I tested a chemical TEAD activator, for its efficacy to promote β-cell regeneration. TT-10 has been previously reported to induce cardiomyocyte regeneration during cardiac infarction. TT-10 promoted the proliferation of β- cells in both mouse and human islets, in an organ donor with T2D, as well as in vivo in mouse pancreatic islets, together with the restoration of functional gene expression in β-cells. This effected was mediated through TEAD. In the last part of my studies, I overexpressed YAP in β-cells in vivo and investigated the effects on β-cells. The expression of YAP correlated with Coxsackieviruses B (CVB) infection, and many YAP-expressing cells show virus positivity or are localised in the immediate vicinity of virus-infected cells in the pancreas of organ donors with T1D and with T1D associated autoantibodies (AAb+). YAP was highly upregulated in both exocrine and endocrine pancreas I in T1D and AAb+ donors. My studies focused on identifying the pathological connection between diabetes and YAP levels in β-cells in pancreas, revealed that chronic and homozygous induction of YAP expression was associated with impaired glucose tolerance, abolished insulin secretion and dedifferentiation of the β-cells in mice. Together, my findings highlight β-cell regeneration for the therapy of diabetes and demonstrate the functional importance of YAP and its transcription factor TEAD in restoring pancreatic islet β-cell mass and proliferation, while YAP’s protective effect becomes opposite in the presence of enteroviral infection.