Hair Follicle Dermal Stem Cell Functions and Potential

项目概要 毛发周期是研究微环境或生态位对成体干细胞 (SC) 调节的绝佳模型， 因为它涉及毛囊 (HF) 的退化、休息和再生。在消退过程中，大多数 HF 上皮细胞 因细胞凋亡而死亡，而间充质真皮乳头 (DP) 细胞群则存活并从 HF 中重新定位 基底到永久上卵泡中的 SC。在休息阶段，来自 DP 的信号对于 激活 SC 以启动正在生长的 HF 的再生。与 DP 接触并包围不断生长的 HF 是 我们最近报道的真皮鞘 (DS) 是 DP 重新定位所必需的特殊平滑肌 和卵泡退化。在 DS 中，最近发现了一个非平滑肌细胞亚群，它也 能够抵抗退化并具有令人感兴趣的 SC 潜力，可以再生 DS 平滑肌并重新生长 HF 和在毛发循环过程中为 DP 谱系贡献细胞。这些细胞被恰当地命名为 HF 真皮 SC （高频DSC）。然而，由于缺乏直接的遗传信息，这些强效细胞的证据在很大程度上是间接的。 针对 hfDSC 细胞消融、标记和追踪以及基因敲除。我们的近期目标是克服 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 hfDSC 对 HF 再生的功能要求？在正常情况下，他们的血统对 DP 的贡献是什么？ 不受干扰的头发循环？伤口愈合过程中 hfDSC 细胞的可塑性是多少？分子有哪些 控制 hfDSC 特性和效力的机制？我们的长期目标是了解 hfDSC 和 DP 如何 生态位细胞控制 SC 功能，并为开发未来的毛发再生疗法提供合理的基础。 我们最近分离了成熟的成熟细胞，对其进行了全转录组表征、基因靶向和实时成像。 DS 揭示了卵泡退化中的关键收缩作用。我们现在已经开发出一种基因驱动程序来研究 其祖细胞 hfDSC 的细胞和分子功能。根据我们的初步数据，我们已经确定 第一次特异性和诱导性靶向 hfDSC 的条件；探索它们的细胞动力学； 定义 hfDSC 的功能要求；首次纯化静态和激活状态的 hfDSC； 定义 hfDSC 特定基因特征；并询问 hfDSC 身份和功能的调节。有了这些 研究中，我们将严格检验 hfDSC 构成有效间充质祖细胞群的假设 高频利基市场。总的来说，这项工作将建立静息期 hfDSC 的遗传靶向，揭示它们的细胞 其他毛发和皮肤间充质细胞的周转率和谱系潜力，并提供分子洞察 hfDSC 基因在周期中的调控和功能。

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.