Transcriptional regulation of skin stem cells and their niche

项目摘要： 这项研究的首要目标是了解头发的机制， 卵泡干细胞（HF-SC）的维持和衰老。HF-SC存在于解剖学上不同的 区域，称为凸起。在生命周期中，HF-SC经历一个多阶段的过程，称为 头发周期，产生毛干和自我更新。在毛发周期的生长期，HF- 干细胞和它们的毛胚祖细胞在毛囊中产生大量的转录放大细胞， 基质的毛球，其中前体的终末分化毛干产生，以燃料 头发生长在退化期，毛囊下部的大多数细胞，包括 基质，经历凋亡，但少数细胞存活并向上移动，以帮助形成新的细胞。 膨胀舱在形成新的隆突隔室时，HF-SC通常停留在 在开始下一个毛发生长期之前的静止休止期。尽管许多 研究已经检查了调节HF-SC自我更新和分化的机制， 对于这些干细胞是如何定量控制毛发生长以及它们的 功能在衰老过程中衰退。在第一个融资周期，我们已经建立了皮肤特异性， Foxc 1和Nfatc 1双敲除作为HF的过早老化模型，并揭示了 HF-SC从它们的隆起生态位逃逸作为HF-SC减少的新机制， 高频小型化。在我们的初步研究中，我们已经产生了一个头发周期阶段特定的 单细胞图谱和纵向单细胞图谱。这些丰富的单细胞 转录组学数据集已经鉴定了迁移生态位（migNiche）的独特细胞群体。 使用活体实时成像跟踪多个HF中单个HF的毛发生长持续时间 在我们的突变体模型中，我们已经获得了实验证据表明HF- SC凸起控制生长期毛发生长的持续时间和HF的大小，并且反过来，定义了生长期毛发的生长。 下一代凸起的大小。在这个提案中，我们将利用我们创新的活体 成像，单细胞基因组工具和基因工程小鼠模型，以了解细胞 毛囊干细胞维持的外在和细胞内在机制。我们将调查 新的HF-SC区室的形成及其对毛发生长的影响（目的1）。然后我们将 阐明FOXC 1/NFATC 1介导的基因表达控制在迁移生态位（目的2）。 最后，我们将阐明HF-SC逃逸的机制和后果（目的3）。我们一起努力， 我们的更新应用程序将为维护提供概念性和机械性的见解 HF-SC通过migNiche介导的细胞外源性机制和细胞内源性 由HF-SC粘附控制的机制。

Project Summary: The overarching goal of the proposed research is to understand the mechanism of hair follicle stem cell (HF-SC) maintenance and aging. HF-SCs reside in an anatomically distinct region, called the bulge. During the lifespan, HF-SCs go through a multi-stage process, called the hair cycle, to generate hair shaft and self-renew. During the anagen phase of hair cycle, HF- SCs and their hair germ progenitors give rise to a large number of transit-amplifying cells in the Matrix of hair bulb, where precursors to terminally differentiated hair shaft are produced, to fuel hair growth. During the catagen phase, most cells in the lower portion of hair follicles, including the Matrix, undergo apoptosis but a few cells survive and move upward to help to form the new bulge compartment. Upon the formation of the new bulge compartment, HF-SCs usually rest in the quiescent telogen phase before initiating the next anagen hair growth. Although many studies have examined mechanisms that regulate self-renewal and differentiation of HF-SCs, it remains poorly understood how these stem cells quantitatively control hair growth and how their functions decline during aging. In the first funding cycle, we have established skin specific, Foxc1 and Nfatc1 double knockout as a premature aging model for HFs and revealed the escape of HF-SCs from their bulge niche as a new mechanism for the reduction of HF-SCs and HF miniaturization. In our preliminary study, we have generated a hair cycle stage-specific single-cell atlas and a longitudinal single-cell atlas during aging. These rich single-cell transcriptomic datasets have identified a unique cell population of migratory niche (migNiche). Using intravital live imaging to track the duration of hair growth for individual HFs across multiple hair cycles in our mutant model, we have obtained experimental evidence that the size of HF- SC bulge controls the duration of anagen hair growth and the size of HFs and, in turn, define the size of the next-generation bulge. In this proposal, we will utilize our innovative intravital imaging, single-cell genomic tools and genetically engineered mouse models to understand cell extrinsic and cell intrinsic mechanisms of hair follicle stem cell maintenance. We will Investigate the formation of new HF-SC compartment and its effect on hair growth (Aim 1). We will then elucidate FOXC1/NFATC1-mediated gene expression control in the migratory niche (Aim 2). Finally, we will elucidate the mechanism and consequence of HF-SC escape (Aim 3). Together, our renewal application will provide conceptual and mechanistic insights into the maintenance of HF-SCs through a cell extrinsic mechanism mediated by migNiche and a cell intrinsic mechanism controlled by HF-SC adhesion.