Coordinated Regulation of Hair Growth and Pigmentation by Dermal Papilla Cells

描述(由申请人提供)：在理解毛乳头细胞(DPC)如何指示异种毛囊干细胞(SCs)以同步方式反应以促进头发健康生长方面，存在着基本的知识空白。毛囊是一种自我更新的微型器官，由不同谱系的毛囊干细胞(包括上皮干细胞和黑素细胞干细胞)的增殖和分化支持。这种差距的持续存在限制了我们设计有效的策略来治疗头发生长障碍，以及在先天性脱发或皮肤创伤的情况下再生毛囊的能力。我研究的长期目标是发现DPC中可用于头发再生和色素沉着的分子途径。本申请的总体目标是确定Wnt/？-catenin信号环的特征，通过该信号环，DPC与毛囊干细胞及其后代相互作用并引导其促进毛发生长。WNT/β-catenin信号活性是EPSCs和MSCs在生长期开始协调激活所必需的。WNT蛋白还可以延长分离的DPC诱导毛发的能力。然而，启动这些活动的内源性Wnt信号的来源和性质仍不清楚。我们的中心假设是，特定的Wnt蛋白首先在生长期的DPC中作为自分泌信号产生，随后在一个相互的信号环中发挥作用，以协调毛囊干细胞的激活以重建着色的头发。其基本原理是，这项研究的成功完成将提供DPC中Wnt蛋白的性质的详细表征，以及DPC中的Wnt/β-catenin信号通过毛囊的正常周期生长引导毛囊干细胞及其后代的机制。这一假说将通过三个具体目标得到验证：1)确定在出生后毛发周期中对Wnt/？-catenin信号做出反应的DPC群体；2)确定DPC中的Wnt蛋白是否需要在出生后毛发周期中激活Wnt/？-catenin信号，并诱导和维持毛发生长和着色；以及3)确定DPC中Wnt/？-catenin信号的激活是否足以调节出生后毛发生长和色素的启动和维持。我们提出的研究具有创新性，因为我们是第一个设计体内小鼠模型系统来探索DPC中Wnt蛋白的性质以及它们作为激活信号启动DPC以诱导毛发并同步激活毛囊EPSCs和MSCs的作用。这项拟议研究的贡献是重大的，因为它将加深我们对DPC作为信号中心在调节色素毛发生长中的作用的理解，并最终可能使在严重皮肤创伤情况下再生毛囊和治疗毛发生长障碍的新策略得以开发。最终，从我们的研究中获得的知识也将有助于更广泛和更深入地了解干细胞生物学和组织工程。

DESCRIPTION (provided by applicant): There is a fundamental knowledge gap in understanding how dermal papilla cells (DPCs) instruct the heterogeneous follicular stem cells (SCs) to react in a synchronized manner for a healthy hair growth. The hair follicle is a self-renewing mini-organ supported by the proliferation and differentiation of follicular SCs of different lineages, including epithelial stem cells (EpSCs) and melanocyte stem cells (MSCs). Continued existence of this gap limits our ability to design the effective strategies for the treatment of hair growth disorder, and for the regeneration of hair follicles in cases of congenita hair loss or skin wounds. The long-term goal of my research is to discover the molecular pathways in DPCs that could be manipulated for hair regeneration and pigmentation. The overall objective in this application is to characterize the Wnt/¿-catenin signaling loop by which DPCs interact with and guide follicular SCs and their progeny to promote hair growth. Wnt/¿-catenin signaling activity is indispensable for the coordinated activation of EpSCs and MSCs at anagen onset. Wnt proteins can also prolong the ability of isolated DPCs to induce hair. However the origin and nature of the endogenous Wnt signals to initiate these activities remain unidentified. Our central hypothesis is that specific Wnt proteins are first generated in DPCs at anagen onset as an autocrine signal, and subsequently function in a reciprocal signaling loop to orchestrate the activation of follicular SCs to rebuild pigmented hair. The rationale is that the successful completion of the proposed research will provide detailed characterization of the nature of Wnt proteins from DPCs and the mechanism by which the Wnt/¿-catenin signaling in DPCs guide follicular SCs and their progeny through the normal cyclic growth of hair follicles. This hypothesis will be tested by pursuing three specific aims: 1) identify the DPC populations that respond to Wnt/¿-catenin signals during the postnatal hair cycle; 2) determine whether Wnt proteins from DPCs are required to activate Wnt/¿-catenin signaling in the postnatal hair cycle and to induce and sustain hair growth and pigmentation; and 3) determine whether the activation of Wnt/¿-catenin signaling in DPCs is sufficient to regulate the initiation and maintenance of postnatal hair growth and pigmentation. Our proposed research is innovative because we are the first to engineer an in vivo mouse model system to probe the nature of Wnt proteins from DPCs and their role as an activating signal to prime DPCs for hair induction and activate follicular EpSCs and MSCs in a synchronized manner. The contribution from this proposed research is significant because it will deepen our understanding of the role of DPCs as a signaling center in the regulation of pigmented hair growth and may ultimately permit the development of novel strategies for regenerating hair follicles in cases of severe skin wounds and for the treatment of hair growth disorders. Ultimately, the knowledge obtained from our research will also contribute to a broader and deeper understanding of stem cell biology and tissue engineering.