Role of pericytes in pancreatic islet fibrosis

摘要 纤维化是2型糖尿病（T2 D）胰岛中非常常见的病变，并可导致进行性糖尿病。 胰岛功能受损。事实上，胰岛微血管系统的缺陷损害了胰岛细胞之间的交换。 内分泌细胞和血液，破坏胰岛结构，并最终导致内分泌细胞死亡。一个重要 微血管的组成部分是周细胞，一种包裹小血液的收缩性平滑肌样细胞 船舶.在不同的器官中，周细胞已被证明分化成肌成纤维细胞，导致纤维化 和器官功能障碍周细胞是否也有助于胰岛中促纤维化肌成纤维细胞的池， 年龄和2型糖尿病尚未确定。我研究的长期目标是了解 胰岛微血管系统在2型糖尿病发病机制中的作用我的K 01研究计划的目标 是为了表征胰岛素抵抗和高胰岛素血症状态下胰岛周细胞的表型， 作为衰老和2型糖尿病，并确定这些变化的原因，使用体外和体内相结合的方法， 体内方法。核心假设是，在衰老和2型糖尿病早期， 暴露于胰岛素加剧了通过周细胞中的哺乳动物雷帕霉素靶（mTOR）的信号传导， 使它们分化成肌成纤维细胞。在我们的模型中，高胰岛素血症的发展是为了补偿 胰岛素抵抗和胰岛周细胞暴露于更高水平的胰岛素。胰岛素过度激活mTOR信号传导 这有利于它们分化成肌成纤维细胞和这些促纤维化细胞的增殖。 中心假设正在两个具体目标中进行检验：1）确定年龄和糖尿病引起的 胰岛周细胞的表型; 2）确定mTOR依赖性胰岛素信号传导在周细胞中的作用 转分化在第一个目标下，我们研究了老年人和2型糖尿病患者周细胞的表型， 来自小鼠和人的胰岛（Almaça等，2018，Cell Metabolism）。此外，使用转基因小鼠， 胰岛血管纤维化和谱系示踪模型，直观地显示了胰岛细胞的表型转变， 周细胞朝向肌成纤维细胞（Mateus Gonçalves等人，2020，Diabetologia）。在第二个目标下，我们 测定胰岛素对胰岛周细胞转化为促纤维化细胞的直接体外和体内作用 肌成纤维细胞此外，我们目前正在体内操纵周细胞中的胰岛素和mTOR信号， 测量对胰岛微血管功能和葡萄糖稳态的影响。这项研究可能会影响 我们对周细胞在胰岛生物学中的作用的认识。在成功完成这一建议后，我们将更好地 了解糖尿病发病机制中周细胞功能障碍和胰岛纤维化之间的联系。

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.