Transcriptional regulation of skin stem cells and their niche

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Project Summary: The overarching goal of the proposed research is to understand the mechanism of hair follicle stem cell (HF-SC) maintenance and aging. HF-SCs reside in an anatomically distinct region, called the bulge. During the lifespan, HF-SCs go through a multi-stage process, called the hair cycle, to generate hair shaft and self-renew. During the anagen phase of hair cycle, HF- SCs and their hair germ progenitors give rise to a large number of transit-amplifying cells in the Matrix of hair bulb, where precursors to terminally differentiated hair shaft are produced, to fuel hair growth. During the catagen phase, most cells in the lower portion of hair follicles, including the Matrix, undergo apoptosis but a few cells survive and move upward to help to form the new bulge compartment. Upon the formation of the new bulge compartment, HF-SCs usually rest in the quiescent telogen phase before initiating the next anagen hair growth. Although many studies have examined mechanisms that regulate self-renewal and differentiation of HF-SCs, it remains poorly understood how these stem cells quantitatively control hair growth and how their functions decline during aging. In the first funding cycle, we have established skin specific, Foxc1 and Nfatc1 double knockout as a premature aging model for HFs and revealed the escape of HF-SCs from their bulge niche as a new mechanism for the reduction of HF-SCs and HF miniaturization. In our preliminary study, we have generated a hair cycle stage-specific single-cell atlas and a longitudinal single-cell atlas during aging. These rich single-cell transcriptomic datasets have identified a unique cell population of migratory niche (migNiche). Using intravital live imaging to track the duration of hair growth for individual HFs across multiple hair cycles in our mutant model, we have obtained experimental evidence that the size of HF- SC bulge controls the duration of anagen hair growth and the size of HFs and, in turn, define the size of the next-generation bulge. In this proposal, we will utilize our innovative intravital imaging, single-cell genomic tools and genetically engineered mouse models to understand cell extrinsic and cell intrinsic mechanisms of hair follicle stem cell maintenance. We will Investigate the formation of new HF-SC compartment and its effect on hair growth (Aim 1). We will then elucidate FOXC1/NFATC1-mediated gene expression control in the migratory niche (Aim 2). Finally, we will elucidate the mechanism and consequence of HF-SC escape (Aim 3). Together, our renewal application will provide conceptual and mechanistic insights into the maintenance of HF-SCs through a cell extrinsic mechanism mediated by migNiche and a cell intrinsic mechanism controlled by HF-SC adhesion.