MCL-1 is essential for hair growth by preventing BAK-mediated apoptosis of activated adult hair follicle stem cells
Hair follicles (HFs) cycle between expansion, regression and quiescence. To investigate the role of MCL-1, a BCL-2 family protein with anti-apoptotic and non-apoptotic functions in this dynamic process, we delete Mcl-1 within the skin epithelium, using both constitutive and inducible systems. Mcl-1 deletion does not impair HF organogenesis but results in gradual hair loss and HF stem cells (HFSC) elimination. Single-cell RNA-seq profiling unveils activated DNA repair and P53 signaling pathways in HFSCs during hair regeneration. Acute Mcl-1 deletion led to the depletion of activated HFSCs. Moreover, the ERBB pathway is found to promote MCL-1 protein expression in HFs. Accordingly, ERBB inhibition depletes activated HFSCs in adult mice. Remarkably, the loss of a single Bak allele rescues Mcl-1 deletion-associated defects in both HFs and mammary glands. These findings emphasize the pivotal role of MCL-1 in inhibiting proliferation stress-induced apoptosis when quiescent stem cells re-enter cell cycling to fuel tissue regeneration. Overall design: Single-cell RNA-seq profiling on the dynamics of adult hair follicles regeneration at 0-hour, 4-hour, 16-hour, 2-day, 4-day, and 6-day post depilation.