247 Metabolic signaling in sebaceous gland homeostasis

Abstract

Organismal aging is associated with typical aging phenotypes with structural changes and functional declines of organs. Hair loss is one of the most typical aging phenotypes in mammals, but the underlying mechanisms are still largely unclear. Here we report that the aging of hair follicles progresses in a step-wise manner with a distinct program in hair follicle stem cells (HFSCs) to cause irreversible hair loss. We found that DNA damage response (DDR) in murine HFSCs cause profound proteolysis of type XIIV collagen (COL17A1), a critical molecule for HFSC maintenance. Systematic fate analysis of those primed HFSCs with genetic stem cell tagging demonstrates that they locally initiate an epidermal differentiation program with the induction of c-MYC and NOTCH1, key regulators of epidermal differentiation within the stem cell niche, without renewing themselves or supplying follicular keratinocytes for hair growth. Those cells migrate from the bulge area through the junctional zone toward the epidermis and are eventually desquamated from the epidermal surface. Strikingly, similar aging processes were prematurely induced by Col17a1 deficiency in HFSCs or in progeric mouse models. In addition, we revealed that human scalps gradually cause hair follicle miniaturization by aging and COL17A1 expression is significantly impaired in miniaturized hair follicles through the provocation of COL17A1 protease by DDR. Furthermore, the entire aging program was significantly rescued by the forced maintenance of COL17A1 in HFSCs of aging mice, demonstrating that progression of such tissue aging programs can be controlled through changes in the expression of key molecule COL17A1 in mammalian somatic stem cells.