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.
The proposed studies will examine the mechanisms by which the protective microenvironment or niche of hair follicle stem cells forms and is maintained. These studies have important implications for understanding, treating and preventing age- or disease-related hair degeneration. This work will further have global relevance for other regenerative tissues in which stem cell niches operate to maintain tissue homeostasis.
|Sennett, Rachel; Rezza, Amélie; Dauber, Katherine L et al. (2014) Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation. Exp Dermatol 23:748-50|