Cellular and molecular mechanisms of hair follicle dermal papilla formation

描述（由申请人提供）：组织稳态对维持器官完整性和功能至关重要，但这些过程背后的分子机制和细胞动力学尚未明确定义。对于在整个生命过程中不断更新的器官系统，多能“成体干细胞”的储存库会自我更新并根据需要进行分化，以产生组成每个复杂组织的不同细胞类型。这些多能细胞是由周围微环境或“生态位细胞”传递的信号维持的。毛囊是一个极好的模型系统，用于探索驱动干细胞和小生境细胞规范和维持的分子机制，因为在胚胎发生期间形成的毛囊在数十年的生命中自然地经过多个阶段的退化和再生。当毛囊不能循环并进入休眠状态时，毛干的产生就会停止，脱发就会随之而来。这种毛囊生产力的下降可能是正常衰老的结果，也可能是皮肤病或全身性疾病的后遗症，但不管潜在的问题是什么，导致脱发的形态学和分子变化通常是不明确的，而且几乎没有有效的药物治疗方法。由于干细胞和小生境细胞群之间的相互作用驱动卵泡循环，任一隔间的破坏都会导致卵泡衰老。更好地了解在头发形态发生和循环过程中发生的动态分子和细胞变化，将揭示治疗年龄或疾病相关脱发的治疗靶点，并更广泛地深入了解在其他持续补充的组织中驱动持续组织稳态的因素。本研究旨在探讨毛囊内真皮乳头形成和维持的细胞动力学和分子机制，这些间充质细胞为上皮干细胞提供重要的生态位信号。我会利用命运映射技术

DESCRIPTION (provided by applicant): Tissue homeostasis is crucial to maintain organ integrity and function, but the molecular mechanisms and cellular dynamics underlying these processes are not yet well-defined. For organ systems that are continuously renewing throughout life, reservoirs of multipotent "adult stem cells" self-renew and differentiate as needed to produce the separate cell types that compose each complex tissue. These multipotent cells are maintained by signals imparted from the surrounding microenvironment or "niche cells". The hair follicle represents an excellent model system in which to explore the molecular mechanisms driving the specification and maintenance of both stem and niche cells, since follicles that are formed during embryogenesis naturally cycle through multiple phases of degeneration and re-growth over decades of life. When follicles fail to cycle and become dormant, hair shaft production ceases and hair loss ensues. Such a decline in follicle productivity can occur as a consequence of normal aging or as a sequela of dermatological or systemic disease, but regardless of the underlying problem, the morphological and molecular changes leading to hair loss are generally ill- defined and there are few effective pharmacological therapies available. As interactions between the stem cell and niche cell populations drive follicle cycling, the breakdown of either compartment leads to follicle senescence. A better understanding of the dynamic molecular and cellular changes that occur in the niche compartment during hair morphogenesis and cycling will reveal therapeutic targets for treating age- or disease- associated hair loss and more broadly provide insight into the factors that drive continued tissue homeostasis in other continuously replenishing tissues. This proposal aims to explore the cellular dynamics and molecular mechanisms of dermal papilla formation and maintenance within the hair follicle, where these mesenchymal cells provide crucial niche signals to support epithelial stem cells. I will utilize fate mapping techniques that employ novel niche-specific genetic tools to trace single cells during morphogenesis and through the first hair cycle, in order to characterize how the hair follicle mesenchyme forms and to detect multipotent niche progenitor cells. I will further use BrdU pulse/chase labeling to defin the proliferative status of niche cells during follicle formation versus cycling. Finally I will islate dermal papilla cells, related dermal sheath cells and their embryonic precursors using established transgenic reporter mice. I will then rigorously analyze global gene expression profiles of these samples in order to define a set of signature genes for distinct mesenchymal populations in nascent and actively growing follicles. This will identify key molecular features that are intrinsically important for establishing and maintaining a functional niche, which in turn supplies signals to promote hair follicle productivity. The strengths of this proposal lie in the innovation of using unique mouse tools to target mesenchymal niche cells within the hair follicle, and the potential to generate translatable findings for future clinical application.