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.

项目摘要 头发循环​​涉及重复的祖细胞中生长毛囊（HF）的显着重塑 死亡和叶子回归，休息和新的头发生长。因此，它是研究回归的绝佳模型 以及由上皮干细胞（SC）和祖细胞执行的再生过程，由 利基微环境。来自真皮乳头（DP）的信号调节祖细胞增殖和分化 在生长的HF的灯泡中，并在其余成长过渡期间诱导头发胚芽中的SC 完全成长的HFS。最近，DP的信号暗示在Catagen期间还诱发祖细胞死亡 回归。在回归过程中，DP本身需要从生长灯泡的底部转移到SC储层 在上HF中。几十年来，如何实现这一目标一直未知。我们以前确定了真皮 鞘（DS）作为一种功能平滑肌，与物理重新安置DP以达到其必不可少的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，这对于推动Catagen回归至关重要的过程。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），这是 以前与DP的TGF信号有关祖细胞死亡。使用其他初步数据我们 然而，发现DP对于修剪祖细胞数是可分配的，并且DS是必不可少的信号 控制植物回归的来源。在我们的研究中，我们将严格检验DS的假设 构成通过TGF信号传导控制头发周期中的回归的信号生态位。我们将有选择地 并在头发生长过程中诱导DS和DP诱导，并明确确定其对Catagen的需求 启动和祖先死亡。我们将探索DS和TGFβ中TGFβ途径成分的表达 祖细胞中的信号传导，建立DS衍生的TGFβ信号在TGFβ1修剪祖细胞修剪中的关键作用 消融并用组合PSMAD2染色质鉴定下游转录靶 免疫沉淀和转座酶可访问的染色质测序分析。最后，我们将确定 tgfβ活化复合物在祖细胞-DS界面上通过smfish和if和if和 DS合同介导的力如何激活全粉状收缩测定中的TGFβ信号传导。 总体而言，这项工作将定义叶鞘的关键生理功能，以控制祖细胞命运，这 可能对开发HF再生方法有用，包括操纵catagen修剪 祖先。