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）调控的极好模型， 因为它涉及毛囊（HF）退化、休息和再生的发作。在退化过程中，大多数HF上皮细胞 间充质毛乳头（DP）细胞簇存活并从HF中重新定位， 基底部至永久性毛囊上部的SC。在休息阶段，来自DP的信号对于 激活所述SC以启动生长的HF的再生。与DP接触并包裹生长的HF是 真皮鞘（DS），我们最近报道，是一个专门的平滑肌必不可少的DP搬迁 和卵泡退化。在DS中，最近发现了一种非平滑肌细胞亚群， 在退化中存活，并具有令人感兴趣的SC再生DS平滑肌的潜力 HF和促进细胞的DP谱系在头发周期。这些细胞被恰当地命名为HF真皮SC （hfDSC）。然而，由于缺乏直接的遗传学证据，这些有效细胞的证据在很大程度上是间接的。 靶向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hfDSC研究和回答几个关键问题的障碍： HF再生的hfDSC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细胞的可塑性是什么？什么是分子 控制hfDSC身份和效力的机制？我们的长期目标是了解hfDSC和DP 小生境细胞支配SC功能，并为开发未来的毛发再生疗法提供合理的基础。 我们最近已经分离出，转录组范围内的特点，遗传靶向和活成像的成熟 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 它们的祖细胞hfDSC的细胞和分子功能。根据我们的初步数据， 首次特异性和诱导性靶向hfDSC的条件;探索其细胞动力学; 定义hfDSC的功能要求;首次纯化处于静止和活化状态的hfDSC; 定义hfDSC特异性基因特征;和询问hfDSC身份和功能的调节。与这些 我们将严格检验hfDSC构成有效间充质祖细胞群的假设 HF的niche。总的来说，这项工作将建立静息期hfDSCs的遗传靶向，揭示它们的细胞增殖， 其他毛发和皮肤间充质细胞的周转和谱系潜力，并提供分子见解， hfDSC基因在周期中的调节和功能。

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.