Role of pericytes in pancreatic islet fibrosis

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Abstract Fibrosis is a very frequent lesion in the islets of type 2 diabetics (T2D) and can contribute to a progressive impairment of islet function. Indeed, defects in the islet microvasculature compromise exchanges between the endocrine cells and the blood, disrupt islet architecture and ultimately lead to endocrine cell death. An important component of the microvasculature is the pericyte, a contractile smooth muscle-like cell that wraps small blood vessels. In different organs, pericytes have been shown to differentiate into myofibroblasts, leading to fibrosis and organ dysfunction. Whether pericytes also contribute to the pool of profibrotic myofibroblasts in islets during aging and type 2 diabetes had not been determined. The long-term goal of my research is to understand the role of the islet microvasculature in the pathogenesis of type 2 diabetes. The objectives of my K01 research proposal were to characterize the phenotype of islet pericytes during insulin resistant and hyperinsulinemic states, such as aging and type 2 diabetes, and determine the cause of those changes, using a combination of in vitro and in vivo approaches. The central hypothesis was that, during aging and early type 2 diabetes, the excessive exposure to insulin exacerbated signaling through the mammalian target of rapamycin (mTOR) in pericytes, which made them differentiate into myofibroblasts. In our model, hyperinsulinemia develops to compensate for insulin resistance and islet pericytes are exposed to higher levels of insulin. Insulin overactivates mTOR signaling in pericytes, which favors their differentiation into myofibroblasts and proliferation of these profibrotic cells.The central hypothesis is being tested in two specific aims: 1) Identify age- and diabetes-induced changes in the phenotype of the islet pericyte; 2) Determine the role of mTOR-dependent insulin signaling in pericyte transdifferentiation. Under the first aim, we have examined the phenotype of pericytes in aged and type 2 diabetic islets from mice and humans (Almaça et al., 2018, Cell Metabolism). Furthermore, using a transgenic mouse model of islet vascular fibrosis and lineage tracing, we directly visualized the phenotypic transition of islet pericytes towards myofibroblasts (Mateus Gonçalves et al., 2020, Diabetologia). Under the second aim, we are determining the direct in vitro and in vivo effects of insulin on the conversion of islet pericytes into profibrotic myofibroblasts. In addition, we are currently manipulating insulin and mTOR signaling in pericytes in vivo and measure the effects on islet microvascular function and glucose homeostasis. The proposed research can impact our knowledge on the role of pericytes in islet biology. Upon successful completion of this proposal, we will better understand the link between pericyte dysfunction and islet fibrosis in the pathogenesis of diabetes.