Hair Follicle Stem Cell SLC3A2 Regulates Epithelial Regenerative Properties

SLC3A2, an essential enhancer of integrin signaling, regulates skin homeostasis. We deleted SLC3A2 in hair follicle stem cells (HFSCs) to get insights into its role in cell-fate decision. Epidermal SLC3A2 is required for stem cell population maintenance. We show that slc3a2 itself is expressed in HFSCs. Deleting this gene in multiple hair follicle stem population (keratin 9, Lrig1) resulted in a drastic loss of HFSCs, leading to hair follicle growth defect. SLC3A2 is required for HFSC proper location. In the absence of SLC3A2, stem cells failed to differentiate into follicular keratinocytes; instead, they adopted an interfollicular epidermis destiny, making SLC3A2 essential for stem cell fate decisions. Hair follicle growth blockade was also associated with decreased fibronectin matrix expression. Using an in vivo skin reconstitution assay, we demonstrate that SLC3A2 preserves HFSC autonomous functions. We found that HFSC SLC3A2 integrin controls stem cell fate and skin regenerative properties, through a YAP/Taz-dependent pathway. Finally, SLC3A2 depletion in primary keratinocytes led to defective sphingomyelin synthesis and reduced CerS4 expression, showing that sphingolipid metabolism, downstream of SLC3A2, is crucial for HFSC compartment establishment.