Regulation of catagen regression and progenitor pruning by the dermal sheath

真皮鞘对退行期回归和祖细胞修剪的调节

• 批准号: 10407589
• 负责人: Michael Rendl
• 金额: $ 51.5万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407589
• 关键词: Ablation; Apoptosis; Biological Assay; Cell Death; Cells; Cessation of life; Chromatin; Complex; Contracts; Data; Dermal; Future; Gene Expression; Genetic; Genetic Transcription; Germ; Goals; Growth; Hair; Hair follicle structure; Integrins; Ligands; Link; Mediating; Mesenchymal; Molecular; Mus; Natural regeneration; Pathway interactions; Phase; Physiological; Positioning Attribute; Process; Publishing; Regulation; Reporter; Rest; Role; Science; Signal Transduction; Signaling Molecule; Skin; Smooth Muscle; Source; Study models; TGFB1 gene; Testing; Transforming Growth Factor beta; Transposase; Work; base; chromatin immunoprecipitation; combinatorial; epithelial stem cell; insight; novel; progenitor; regenerative approach; regenerative therapy; stem cells; tongue papilla; transcriptome

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.

项目概要 毛发周期涉及在祖细胞的重复阶段中不断生长的毛囊 (HF) 的显着重塑 因此，它是研究退化的绝佳模型。 和再生过程由上皮干细胞（SC）和祖细胞执行并受 来自真皮乳头 (DP) 的信号调节祖细胞增殖和分化。 生长中的 HF 的球茎中，并在休息到生长过渡期间诱导毛胚中的 SC 再生 最近，来自 DP 的信号也被认为在退行期诱导祖细胞死亡。 回归期间，DP 本身需要从正在生长的球茎基部重新定位到 SC 水库。 几十年来，我们一直不知道这是如何实现的。 鞘 (DS) 作为功能性平滑肌，收缩以物理重新定位 DP 以达到其必要的 SC- 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，这个过程对于推动退行期的回归同样重要。我们发现，DS。 动态产生许多信号分子，包括转化生长因子β（TGF）， 先前通过来自 DP 的 TGF 信号与祖细胞死亡有关。 然而，我们发现 DP 对于修剪祖细胞数量来说是可有可无的，而 DS 是必不可少的信号 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 TGF 信号控制头发周期的退化。 并在毛发生长过程中诱导消融 DS 和 DP，并明确确定它们对退行期的需求 我们将探讨 DS 和 TGFβ 中 TGFβ 途径成分的表达。 祖细胞中的信号传导，确定 DS 衍生的 TGFβ 信号传导在 Tgfβ1 修剪祖细胞中的关键作用 使用组合 pSmad2 染色质进行消融并识别下游转录靶标 最后，我们将确定免疫沉淀和转座酶可访问的染色质测序分析。 通过 smFISH 和 IF 检测祖细胞-DS 界面处 TGFβ 激活复合物的分子成分，以及 破译 DS 收缩介​​导的力如何在全卵泡收缩测定中激活 TGFβ 信号传导。 总的来说，这项工作将定义卵泡鞘调节祖细胞命运的关键生理功能， 可能有助于开发 HF 再生方法，包括操纵退行期修剪 祖先。