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MCL‑1 safeguards activated hair follicle stem cells to enable adult hair regeneration

Author

Listed:
  • Hui San Chin

    (Duke‑NUS Medical School)

  • Jinming Cheng

    (The Walter and Eliza Hall Institute of Medical Research
    The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Shih Han Hsu

    (Duke‑NUS Medical School)

  • Guo Guang Lum

    (Duke‑NUS Medical School)

  • Maria TK Zaldivia

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Sarmilla Nelameham

    (Duke‑NUS Medical School)

  • Fusheng Guo

    (Duke‑NUS Medical School)

  • Keerthana Mallavarapu

    (Duke‑NUS Medical School)

  • Felicity C. Jackling

    (The Walter and Eliza Hall Institute of Medical Research)

  • Jicheng Yang

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Jonathan S. L. Tan

    (Agency for Science Technology and Research (A*STAR))

  • Prabha Sampath

    (Duke‑NUS Medical School
    Agency for Science Technology and Research (A*STAR)
    Agency for Science Technology and Research (A*STAR))

  • Nick Barker

    (Agency for Science, Technology and Research (A*STAR)
    National University of Singapore)

  • Gordon K. Smyth

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Geoffrey J. Lindeman

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne
    The Royal Melbourne Hospital
    Peter MacCallum Cancer Centre)

  • Andreas Strasser

    (The University of Melbourne
    The Walter and Eliza Hall Institute of Medical Research)

  • Jane E. Visvader

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Yunshun Chen

    (The Walter and Eliza Hall Institute of Medical Research
    The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Ting Chen

    (National Institute of Biological Sciences)

  • Nai Yang Fu

    (Duke‑NUS Medical School
    The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne
    National University of Singapore)

Abstract

Hair follicles cycle through expansion, regression and quiescence. To investigate the role of MCL‑1, a BCL‑2 family protein with anti‑apoptotic and apoptosis‑unrelated functions, we delete Mcl‑1 within the skin epithelium using constitutive and inducible systems. Constitutive Mcl‑1 deletion does not impair hair follicle organogenesis but leads to gradual hair loss and elimination of hair follicle stem cells. Acute Mcl‑1 deletion rapidly depletes activated hair follicle stem cells and completely blocks depilation‑induced hair regeneration in adult mice, while quiescent hair follicle stem cells remain unaffected. Single‑cell RNA‑seq profiling reveals the engagement of P53 and DNA mismatch repair signaling in hair follicle stem cells upon depilation‑induced activation. Trp53 deletion rescues hair regeneration defects caused by acute Mcl‑1 deletion, highlighting a critical interplay between P53 and MCL‑1 in balancing proliferation and death. The ERBB pathway plays a central role in sustaining the survival of adult activated hair follicle stem cells by promoting MCL‑1 protein expression. Remarkably, the loss of a single Bak allele, a pro‑apoptotic Bcl‑2 effector gene, rescues Mcl‑1 deletion‑induced defects in both hair follicles and mammary glands. These findings demonstrate the pivotal role of MCL‑1 in inhibiting proliferation stress‑induced apoptosis when quiescent stem cells activate to fuel tissue regeneration.

Suggested Citation

  • Hui San Chin & Jinming Cheng & Shih Han Hsu & Guo Guang Lum & Maria TK Zaldivia & Sarmilla Nelameham & Fusheng Guo & Keerthana Mallavarapu & Felicity C. Jackling & Jicheng Yang & Jonathan S. L. Tan & , 2025. "MCL‑1 safeguards activated hair follicle stem cells to enable adult hair regeneration," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58150-5
    DOI: 10.1038/s41467-025-58150-5
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    References listed on IDEAS

    as
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    Full references (including those not matched with items on IDEAS)

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