Restoring hair follicle stem cell fate and heterogeneity outside their native niche

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PROJECT SUMMARY Adult stem cells (SCs) reside in defined niches and depend on microenvironmental cues to instruct their behavior. The hair follicle (HF) is an excellent model system to study a rich set of SC-niche interactions as it undergoes stereotypic regenerative cycles. This self-contained mini-organ utilizes high levels of spatial organization and compartmentalization to promote SC fate determination along HF lineages. However, when hair follicle stem cells (HFSCs) become isolated from their niche, they lose their identity and display a wide-ranging plasticity that can produce all lineages of the skin. This multipotent state has long acted as a barrier to restoring HFSC identity when the niche becomes disrupted, despite a wealth of information regarding the signals that control HFSC behavior. To overcome this challenge, I have built upon our lab’s recent discovery that cultured HFSCs exhibit a wound-like epigenetic signature and hypothesized that targeting the pathways responsible for driving the wound response would permit the re-acquisition of HFSC identity. Here, I present here the development of a platform that reinstates the homeostatic identify of HFSCs, made possible through my identification of niche signals that lie at the intersection between tissue regeneration and wound-related plasticity. My preliminary data demonstrate the efficacy of targeting these pathways to resolve the wound signature and restore their sensitivity to local cues that support the acquisition of a full suite of differentiated HF cell types. In this proposal, I will examine the resulting heterogeneity of HFSC fates in response to optimized niche signals using single cell transcriptomics. My developing bioinformatic skillset will allow me to compare these cell fates with their in vivo counterparts (Aim I). Next, I will dissect the mechanistic role played by retinoic acid (RA), an essential metabolite required for HFSC identity and self-renewal. By focusing on the transcriptional effectors of RA, I will functionally define how RA availability impacts HF cycling and wound-induced follicular neogenesis (Aim II). Lastly, I will apply this platform to human patient samples and functionally dissect HFSC interactions with their dermal niche in newly engineered skin (Aim III). In total, this work will mechanistically define the minimal requirements necessary for human HFSC self-renewal and differentiation. If successful, my research has the potential to rapidly model and test hypotheses related to human HF disorders, accelerate therapeutic efforts aimed at achieving HF morphogenesis, and ultimately regenerate the complete integumentary system.