Abstract P51: MCL-1 safeguards activated hair follicle stem cells to enable adult hair regeneration

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 apoptosis-unrelated functions in this dynamic process, we deleted Mcl-1 within the skin epithelium using both constitutive and inducible systems. Constitutive deletion of Mcl-1 did not impair HF organogenesis but resulted in gradual hair loss and elimination of HF stem cells (HFSC) while acute Mcl-1 deletion rapidly depleted activated HFSCs in adult mice. Single-cell RNA-seq profiling revealed that HFSCs are under proliferation-associated stress during depilation-induced anagen. The ERBB pathway was shown to play a central function in conferring the survival of adult activated HFSCs through promoting MCL-1 protein expression. Remarkably, the loss of a single Bak allele rescued Mcl-1 deletion-induced defects in HFs. These findings demonstrate the pivotal role of MCL-1 in inhibiting stress-induced apoptosis when quiescent stem cells undergo activation to fuel tissue regeneration. Citation Format: Hui San Chin, Jinming Cheng, Shih Han Hsu, Guo Guang Lum, Maria TK Zaldiva, Fusheng Guo, Keerthana Mallavarapu, Felicity C. Jackling, Gordon K. Smyth, Geoffrey J. Lindeman, Andreas Strasser, Jane E. Visvader, Yunshun Chen, Ting Chen, Nai Yang Fu. MCL-1 safeguards activated hair follicle stem cells to enable adult hair regeneration [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P51.