Mechanisms that regulate adipocyte stem cell behavior in the skin

During mouse models of skin infection, injury, and hair regrowth, adipogenesis is initiated via both activation of adipocyte precursor cells (APCs) and the growth of pre-existing mature adipocytes. However, the mechanisms that regulate dermal adipose tissue are not well understood. Here, we show that PDGFA signaling maintains dermal adipose tissue by initiating the proliferation of dermal adipocyte stem cells (dASCs). Prior to the initiation of the hair follicle cycle and generation of new mature adipocytes, Pdgfa is upregulated in the skin and dASCs are activated to proliferate before their preadipocyte progeny. During chronological aging and repeated depilation, when dermal adipose tissue is reduced, dASCs are not maintained, and Pdgfa is downregulated. Conditional deletion of Pdgfa in dermal cells including APCs accelerated these changes, resulting in reduced dermal adipose tissue and dASC cell number. In vitro experiments reveal that PDGFA signals through PI3K to induce proliferation and elicits a unique transcriptional signature in FACS-purified APCs, regulating genes associated with proliferation and adipocyte differentiation. Interestingly, loss of REDD1 (and inhibitor of the mTORC1 complex downstream of PI3K/AKT) resulted in increased dermal adipose tissue in vivo and higher capacity to undergo adipogenesis in APCs in vitro, suggesting that the regulation of the PI3K/AKT/mTOR pathway is key to maintain the homeostasis of the adipose tissue in the skin. These studies reveal novel mechanisms by which APCs are controlled in the skin and may be relevant for defects associated with age-related defects in infection, wound healing, and hair growth.