Regulation of catagen regression and progenitor pruning by the dermal sheath

项目摘要 毛发周期包括生长毛囊(HF)在祖细胞的重复阶段中的显著重塑 死亡和毛囊退化，休息和新的头发生长。因此，它是研究回归的一个很好的模型 和再生过程由上皮干细胞(SC)和祖细胞执行，并受 生态位微环境。毛乳头(DP)信号调节祖细胞的增殖和分化 在生长中的HFs的鳞茎中，并在从静止到生长的转变过程中诱导毛胚中的SCs再生 完全生长的高血压病。最近，来自DP的信号被牵连到在退变过程中也诱导祖细胞死亡 回归。在退化过程中，DP本身需要从不断生长的鳞茎的底部重新定位到SC水库 在较高的高频。几十年来，人们一直不知道这是如何实现的。我们之前确认了真皮 鞘(DS)作为一种功能性的平滑肌，收缩以物理地重新定位DP，以达到其基本的SC- 相邻位置。在这里，我们将测试DS是否是调节祖细胞的潜在信号源 死亡，这是一个同样重要的过程，推动退化剂。我们发现DS 动态产生许多信号分子，包括转化生长因子β(转化生长因子)。 之前通过转化生长因子信号从DP牵连到祖细胞死亡。有了更多的初步数据，我们 然而，发现DP对于修剪祖细胞数量是可有可无的，DS是基本信号 调节卵泡退行性变的来源。在我们的研究中，我们将严格检验DS的假设 构成一个信号生态位，通过转化生长因子信号控制毛发周期的倒退。我们将有选择地 并在毛发生长过程中诱导消融DS和DP，明确确定它们对退化剂的需求 启蒙和先祖死亡。我们将探讨转化生长因子β通路成分在DS和转化生长因子β中的表达。 在祖细胞中的信号，建立DS衍生的转化生长因子β信号在转化生长因子β1修剪祖细胞中的关键作用 利用组合pSmad2染色质消融和识别下游转录靶点 免疫沉淀和转座酶可及染色质测序分析。最后，我们将确定 SmFISH和IF检测转化生长因子β激活复合体在前体-DS界面的分子组成 破译DS收缩介导力如何在全卵泡收缩试验中激活转化生长因子β信号。 总体而言，这项工作将确定卵泡鞘调节祖细胞命运的关键生理功能，即 可能对开发HF再生方法很有用，包括操纵卡特兰修剪 祖先。

Project Summary The hair cycle involves remarkable remodeling of growing hair follicles (HF) in repeated phases of progenitor death and follicle regression, rest and new hair growth. It is therefore an excellent model for studying regression and regeneration processes that are executed by epithelial stem cells (SC) and progenitors and regulated by the niche microenvironment. Signals from the dermal papilla (DP) regulate progenitor proliferation and differentiation in the bulb of growing HFs, and induce SCs in the hair germ during the rest-to-growth transition to regenerate fully growing HFs. Recently, signals from the DP were implicated to induce also progenitor death during catagen regression. During regression, the DP itself needs to relocate from the base of growing bulbs to the SC reservoir in the upper HF. How this is accomplished has been unknown for decades. We previously identified the dermal sheath (DS) as a functional smooth muscle that contracts to physically relocate the DP to reach its essential SC- adjacent position. Here, we will test whether the DS is a potential signaling source that regulates progenitor death, a process equally essential for propelling catagen regression. We have discovered that the DS dynamically produces many signaling molecules including transforming growth factor beta (TGF), which was previously implicated in progenitor death by TGF signals from the DP. With additional preliminary data we found, however, that the DP is dispensable for pruning progenitor numbers and that the DS is the essential signal source for regulating follicle regression. In our studies, we will rigorously test the hypothesis that the DS constitutes a signaling niche that through TGF signaling controls regression in the hair cycle. We will selectively and inducibly ablate the DS and DP during hair growth and unequivocally determine their requirement for catagen initiation and progenitor death. We will explore expression of TGFβ pathway components in the DS and TGFβ signaling in the progenitors, establish a key role of DS-derived TGFβ signaling in progenitor pruning by Tgfβ1 ablations and identify downstream transcriptional targets with combinatorial pSmad2 chromatin immunoprecipitation and transposase-accessible chromatin sequencing analyses. Finally, we will determine the molecular components of the TGFβ activation complex at the progenitor-DS interface by smFISH and IF, and decipher how DS contraction-mediated forces activate TGFβ signaling in whole-follicle contraction assays. Overall, this work will define key physiological functions of the follicle sheath for regulating progenitor fate, which may be useful for developing HF regenerative approaches, including manipulating catagen pruning of progenitors.