Molecular Regulation of Skin Stem Cell Function During Hair Growth and Tumorigenesis

The cellular and molecular mechanisms regulating stem cell (SC) activity during tissue homeostasis are not fully understood. In most tissues, the prevailing view is that stem cell (SC) niches are generated by signals from within the nearby tissue environment. Here, we define genetic changes altered in hair follicle (HF) SCs in mice treated with a potent SC activator, cyclosporine A (CSA), which inhibits the phosphatase calcineurin (CN) and the activity of the transcription factor Nfatc1. We show that CN/Nfatc1 regulates expression of prolactin receptor (Prlr), and that canonical activation of Prlr and its downstream signaling via Jak/Stat5 drives quiescence of HF SCs during pregnancy and lactation, when serum prolactin (Prl) levels are highly elevated. Using Prl injections and genetic/pharmacological loss of function experiments in mice, we show that Prl signaling stalls follicular SC activation through its activity in the skin epithelium. Our findings define a unique CN-Nfatc1-Prlr-Stat5 molecular circuitry that promotes persistent SC quiescence in the skin.;In addition to their roles in tissue maintenance, SCs have been implicated in tumorigenesis. In the skin, HF SCs can act as cells of origin for squamous cell carcinomas (SCCs). Interestingly, patients treated with CSA exhibit enhanced HF growth along with an increased incidence of SCC. To test if CN/Nfatc1 signaling in HF SCs functionally inhibits skin tumorigenesis, we harness a chemical carcinogenesis model to induce skin tumors in mice lacking Nfatc1 specifically in the epidermis. Surprisingly, we find that the loss of Nfatc1 in the skin results in increased resistance to chemically induced tumors. Further analysis reveals that Nfatc1 plays a role in tumor initiation, yet is dispensable for tumor promotion. Combining lineage tracing analyses with gene expression profiling, we find that Nfatc1 promotes bulge SC contribution to skin tumors and upregulates genes involved in cell adhesion and migration. We uncover Periostin (Postn) as a novel target gene of Nfatc1 in the skin and demonstrate that Nfatc1 enhances keratinocyte migration. Together, these findings elucidate novel roles for Nfatc1 in HF SCs during tissue homeostasis and tumor initiation in the skin.