PDGF-regulated cell fate and dermal fibrosis

当过度活跃的间充质细胞产生多余的胶原蛋白以取代功能组织时，就会发生纤维化。 皮肤是由异常伤口愈合、移植物抗宿主病和金黄色葡萄球菌引起的纤维化的主要靶点。 获得豁免权。在一些器官中，纤维化伴随着储脂细胞的消失，并取代- 这表明成纤维细胞-脂肪细胞的命运失调。有必要 更好地了解纤维化的机制，因为我们缺乏针对特定目标的治疗策略 大多数疾病的纤维化过程。升高的血小板衍生生长因子(PDGF)信号是 纤维增生性疾病的主要驱动因素。有两种受体，即血小板衍生生长因子受体α(PDGFRα)和β (PDGFFRβ)，它们有许多共同之处，但它们的调控不同，具有不同的细胞效应 这些都没有在纤维化文献中得到解决。申请人实验室的结果指向PDGFRα 与PDGFRβ相比，它是小鼠肝纤维化的主要调节因子。更具体地说，在真皮来源的祖细胞中 在细胞中，PDGFRα的激活阻止脂肪生成，并诱导细胞分化为促纤维化细胞。怎么- 迄今为止，这种细胞命运转换背后的信号和转录机制尚不清楚。它也保留了下来 以测试去除PDGFRα是否可以改善组织对损伤的反应，从而减少纤维化 并增加脂肪细胞的再生。这个项目背后的假设是，PDGFRα调节 PI3K/Akt/mTor信号通路和一种新的PDGFRα-2在肝纤维化和脂肪生成中的平衡 调节转录因子。AIM 1将使用真皮来源的间充质祖细胞(MPC)作为模型 系统调查PDGFRα调节的PI3K/AKT/mTOR信号是否是必需的，并且对于 细胞命运开关。目的2探讨一种新的PDGFRα调控的转录因子在纤维脂肪形成中的作用 Fate，使用MPC和小鼠作为模型系统，并确定PDGFRα如何调节MPC中的这一新因素。 目的3将研究具有PDGFRα功能获得和丧失突变的小鼠皮肤伤口愈合，以确定 PDGFRα调控瘢痕形成的过程。突变细胞将被绘制命运图以确定如何 在体内，不同水平的PDGFRα活性调节纤维成脂的命运。这项工作有望揭示如何 PDGFRα信号通路介导其对真皮祖细胞的促纤维化/抗脂肪生成作用。这个 诱导间充质细胞走向纤维化的信号通路的发现将为发展提供信息。 开发新的治疗方法。了解DNA结合因子如何调控MPC的命运将有 对核心纤维化机制的理解产生重大影响。并确定PDGFRα在其中的具体作用 疤痕的形成将开始将其确立为治疗的分子靶点。由此产生的可泛化 了解纤维成脂的命运是如何被控制的，将会促进结构和功能的恢复 器官受损。

Fibrosis occurs when overactive mesenchymal cells generate excess collagen that replaces functional tissue. The skin is a major target of fibrosis resulting from aberrant wound healing, graft-versus-host disease, and au- toimmunity. In some organs, fibrosis is accompanied by the disappearance of lipid-storing cells and replace- ment with pro-fibrotic cells, which suggests a dysregulation of fibroblast-adipocyte cell fate. There is a need for better understanding of the mechanisms of fibrosis because we lack treatment strategies that specifically target the fibrogenic process in most diseases. Elevated platelet-derived growth factor (PDGF) signaling is one of the major drivers of fibroproliferative disorders. There are two receptors, PDGF receptor-α (PDGFRα) and β (PDGFRβ), which have much in common but they are regulated differently and have distinct cellular effects that have not been addressed in the fibrosis literature. Results from the applicant's laboratory point to PDGFRα as the major regulator of fibrosis in mice compared to PDGFRβ. More specifically, in dermis-derived progenitor cells, PDGFRα activation blocks adipogenesis and induces the cells to differentiate into pro-fibrotic cells. How- ever, the signaling and transcriptional mechanisms underlying this cell fate switch are unknown. It also remains to be tested whether removal of PDGFRα can improve the tissue response to injury, resulting in less fibrosis and increased regeneration of adipocytes. The hypothesis underlying this project is that PDGFRα regulates the balance of fibrosis versus adipogenesis through the PI3K/Akt/mTOR signaling pathway and a new PDGFRα- regulated transcription factor. Aim 1 will use dermis-derived mesenchymal progenitor cells (MPCs) as a model system to investigate whether PDGFRα-regulated PI3K/Akt/mTOR signaling is required and sufficient for the cell-fate switch. Aim 2 will explore the role of a new PDGFRα-regulated transcription factor in fibro-adipogenic fate, using MPCs and mice as model systems, and determine how PDGFRα regulates this new factor in MPCs. Aim 3 will study dermal wound healing in mice with gain- and loss-of-function mutations in PDGFRα to identify the processes by which PDGFRα regulates scar formation. Mutant cells will be fate mapped to determine how different levels of PDGFRα activity regulate fibro-adipogenic fate in vivo. This work is expected to reveal how the PDGFRα signaling pathway mediates its pro-fibrotic/anti-adipogenic effects on dermal progenitor cells. The discovery of signaling pathways that induce mesenchymal cells towards a profibrotic fate will inform the devel- opment of new therapeutic approaches. Knowledge of how DNA-binding factors regulate MPC fate will have major impact on the understanding of core fibrosis mechanisms. And identifying the specific role of PDGFRα in scar formation will begin to establish it as a molecular target for therapy. The resulting generalizable knowledge about how fibro-adipogenic fate is controlled will improve the restoration of structure and function to damaged organs.