Hair Follicle Dermal Stem Cell Functions and Potential

项目摘要 毛发周期是研究微环境或生态位对成体干细胞(SC)调控的极佳模型。 因为它涉及一连串的毛囊(HF)退化、休息和再生。在退化过程中，大多数HF上皮细胞 间充质毛乳头(DP)细胞团存活并从HF移位时因细胞凋亡而死亡 位于永久上部卵泡中的干细胞的底部。在休眠阶段，来自DP的信号对 激活干细胞以启动生长中的HF的再生。与DP接触并包围不断增长的HFs是 真皮鞘(DS)是DP移位所必需的一种特殊的平滑肌 和卵泡退行性变。在DS内，最近发现了一个非平滑肌细胞亚群，也 在退行性病变中存活下来，并具有令人感兴趣的再生DS平滑肌的SC潜力 HFS和在毛发周期中为DP谱系贡献细胞。这些细胞被恰当地命名为HF真皮干细胞 (HfDSCs)。然而，这些有效细胞的证据大多是间接的，因为缺乏直接的基因 靶向hfDSC细胞的消融、标记和示踪以及基因敲除。我们当前的目标是克服 这是实现直接功能性hfDSC研究并回答几个关键问题的障碍：什么是 HfDSCs对HF再生的功能要求？在正常情况下，他们对民主党的血统贡献是什么？ 泰然自若的骑行头发？创面愈合过程中hfDSC细胞的可塑性如何？分子是什么？ 控制hfDSC身份和效力的机制？我们的长期目标是了解hfdscs和dp如何 利基细胞控制干细胞的功能，并为开发未来的头发再生疗法提供合理的基础。 我们最近分离出了转录组范围的特征，具有基因靶向性，并对成熟的 以揭示卵泡收缩在卵泡退变中的关键作用。我们现在已经开发了一种基因驱动程序来研究 它们的祖细胞hfDSCs的细胞和分子功能。根据我们的初步数据，我们已经确定 首次特异性、诱导性靶向hfDSC的条件；细胞动力学研究； 明确hfDSC的功能需求；首次提纯处于静止和激活状态的hfDSC； 定义hfDSC特异的基因信号；并询问hfDSC的身份和功能的调节。有了这些 研究中，我们将严格检验hfDSC构成强大的间充质祖细胞群体的假设。 在高频利基市场上。总体而言，这项工作将建立静止期hfDSC的基因靶向，揭示其细胞 其他毛发和皮肤间充质细胞的周转和谱系潜力，并提供对 HfDSC基因在细胞周期中的调控和作用。

Project Summary The hair cycle is an excellent model to study adult stem cell (SC) regulation by the microenvironment or niche, as it involves bouts of hair follicle (HF) regression, rest and regrowth. During regression, most HF epithelial cells die by apoptosis while the mesenchymal dermal papilla (DP) cell cluster survives and relocates from the HF base to the SCs in the permanent upper follicle. During the resting phase, signals from the DP are critical for activating the SCs to initiate regeneration of a growing HF. In contact with the DP and encasing growing HFs is the dermal sheath (DS), which we recently reported is a specialized smooth muscle essential for DP relocation and follicle regression. Within the DS, a non-smooth muscle cell subpopulation was recently discovered that also survives regression and has the intriguing SC potential for regenerating the DS smooth muscle of re-growing HFs and for contributing cells to the DP lineage during hair cycling. The cells were aptly named HF dermal SCs (hfDSCs). However, the evidence for these potent cells has been largely indirect due to the lack of direct genetic targeting for hfDSC cell ablation, labeling and tracing and for gene knockouts. Our immediate goal is to overcome this roadblock for enabling direct functional hfDSC studies and answering several key questions: What is the functional requirement of hfDSCs for HF regrowth? What is their lineage contribution to the DP during normal unperturbed hair cycling? What is the hfDSC cell plasticity during wound healing? What are the molecular mechanisms that control hfDSC identity and potency? Our long-term goal is to understand how hfDSCs and DP niche cells govern SC functions and to provide a rational basis for developing future hair regenerative therapies. We have recently isolated, transcriptome-wide characterized, genetically targeted and live imaged the mature DS to uncover a key contractile role in follicle regression. We have now developed a genetic driver to study the cellular and molecular functions of their progenitors, the hfDSCs. With our preliminary data we have established the conditions to specifically and inducibly target for the first time the hfDSCs; explore their cellular dynamics; define the functional requirement of hfDSC; purify for the first time hfDSCs in their quiescent and activated states; define hfDSC-specific gene signatures; and interrogate the regulation of hfDSC identity and function. With these studies we will rigorously test the hypothesis that hfDSCs constitute a potent mesenchymal progenitor population of the HF niche. Overall, this work will establish genetic targeting of resting-phase hfDSCs, reveal their cellular turnover and lineage potential for other hair and skin mesenchymal cells and provide molecular insight into hfDSC gene regulation and function during the cycle.