IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58150-5.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58150-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58150-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Panteleimon Rompolas & Kailin R. Mesa & Valentina Greco, 2013. "Spatial organization within a niche as a determinant of stem-cell fate," Nature, Nature, vol. 502(7472), pages 513-518, October.
    2. Gioele La Manno & Ruslan Soldatov & Amit Zeisel & Emelie Braun & Hannah Hochgerner & Viktor Petukhov & Katja Lidschreiber & Maria E. Kastriti & Peter Lönnerberg & Alessandro Furlan & Jean Fan & Lars E, 2018. "RNA velocity of single cells," Nature, Nature, vol. 560(7719), pages 494-498, August.
    3. Philippe Bouillet & Jared F. Purton & Dale I. Godfrey & Li-Chen Zhang & Leigh Coultas & Hamsa Puthalakath & Marc Pellegrini & Suzanne Cory & Jerry M. Adams & Andreas Strasser, 2002. "BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes," Nature, Nature, vol. 415(6874), pages 922-926, February.
    4. Mark Shackleton & François Vaillant & Kaylene J. Simpson & John Stingl & Gordon K. Smyth & Marie-Liesse Asselin-Labat & Li Wu & Geoffrey J. Lindeman & Jane E. Visvader, 2006. "Generation of a functional mammary gland from a single stem cell," Nature, Nature, vol. 439(7072), pages 84-88, January.
    5. Kailin R. Mesa & Panteleimon Rompolas & Giovanni Zito & Peggy Myung & Thomas Y. Sun & Samara Brown & David G. Gonzalez & Krastan B. Blagoev & Ann M. Haberman & Valentina Greco, 2015. "Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool," Nature, Nature, vol. 522(7554), pages 94-97, June.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Huanhuan Tan & Weixu Wang & Congjin Zhou & Yanfeng Wang & Shu Zhang & Pinglan Yang & Rui Guo & Wei Chen & Jinwen Zhang & Lan Ye & Yiqiang Cui & Ting Ni & Ke Zheng, 2023. "Single-cell RNA-seq uncovers dynamic processes orchestrated by RNA-binding protein DDX43 in chromatin remodeling during spermiogenesis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Yanchuan Li & Huamei Li & Cheng Peng & Ge Meng & Yijun Lu & Honglin Liu & Li Cui & Huan Zhou & Zhu Xu & Lingyun Sun & Lihong Liu & Qing Xiong & Beicheng Sun & Shiping Jiao, 2024. "Unraveling the spatial organization and development of human thymocytes through integration of spatial transcriptomics and single-cell multi-omics profiling," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    3. Chen Jiang & Alessia Centonze & Yura Song & Antonius Chrisnandy & Elisavet Tika & Saba Rezakhani & Zahra Zahedi & Gaëlle Bouvencourt & Christine Dubois & Alexandra Van Keymeulen & Matthias Lütolf & Al, 2024. "Collagen signaling and matrix stiffness regulate multipotency in glandular epithelial stem cells in mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Christoph Ziegenhain & Rickard Sandberg, 2021. "BAMboozle removes genetic variation from human sequence data for open data sharing," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    5. Yoshiaki Yasumizu & Naganari Ohkura & Hisashi Murata & Makoto Kinoshita & Soichiro Funaki & Satoshi Nojima & Kansuke Kido & Masaharu Kohara & Daisuke Motooka & Daisuke Okuzaki & Shuji Suganami & Eriko, 2022. "Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Lichun Ma & Sophia Heinrich & Limin Wang & Friederike L. Keggenhoff & Subreen Khatib & Marshonna Forgues & Michael Kelly & Stephen M. Hewitt & Areeba Saif & Jonathan M. Hernandez & Donna Mabry & Roman, 2022. "Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Keyong Sun & Runda Xu & Fuhai Ma & Naixue Yang & Yang Li & Xiaofeng Sun & Peng Jin & Wenzhe Kang & Lemei Jia & Jianping Xiong & Haitao Hu & Yantao Tian & Xun Lan, 2022. "scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    8. David G. Priest & Takeshi Ebihara & Janyerkye Tulyeu & Jonas N. Søndergaard & Shuhei Sakakibara & Fuminori Sugihara & Shunichiro Nakao & Yuki Togami & Jumpei Yoshimura & Hiroshi Ito & Shinya Onishi & , 2024. "Atypical and non-classical CD45RBlo memory B cells are the majority of circulating SARS-CoV-2 specific B cells following mRNA vaccination or COVID-19," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    9. Jeff Yat-Fai Chung & Philip Chiu-Tsun Tang & Max Kam-Kwan Chan & Vivian Weiwen Xue & Xiao-Ru Huang & Calvin Sze-Hang Ng & Dongmei Zhang & Kam-Tong Leung & Chun-Kwok Wong & Tin-Lap Lee & Eric W-F Lam &, 2023. "Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Fabian Peisker & Maurice Halder & James Nagai & Susanne Ziegler & Nadine Kaesler & Konrad Hoeft & Ronghui Li & Eric M. J. Bindels & Christoph Kuppe & Julia Moellmann & Michael Lehrke & Christian Stopp, 2022. "Mapping the cardiac vascular niche in heart failure," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    11. Hien Bui & Simon Andersson & Agustin Sola-Carvajal & Tommaso Marchi & Eliisa Vähäkangas & Minna Holopainen & Andrew H. House & Bohdana M. Rovenko & Johanna I. Englund & Maria Kasper & Emilia Kuuluvain, 2025. "Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    12. Ana Sofia Rocha & Alejandro Collado-Solé & Osvaldo Graña-Castro & Jaime Redondo-Pedraza & Gonzalo Soria-Alcaide & Alex Cordero & Patricia G. Santamaría & Eva González-Suárez, 2023. "Luminal Rank loss decreases cell fitness leading to basal cell bipotency in parous mammary glands," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    13. Yan Tang & David J. Kwiatkowski & Elizabeth P. Henske, 2022. "Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    14. Jun Dai & Shuyu Zheng & Matías M. Falco & Jie Bao & Johanna Eriksson & Sanna Pikkusaari & Sofia Forstén & Jing Jiang & Wenyu Wang & Luping Gao & Fernando Perez-Villatoro & Olli Dufva & Khalid Saeed & , 2024. "Tracing back primed resistance in cancer via sister cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    15. Ryuki Shimada & Yuzuru Kato & Naoki Takeda & Sayoko Fujimura & Kei-ichiro Yasunaga & Shingo Usuki & Hitoshi Niwa & Kimi Araki & Kei-ichiro Ishiguro, 2023. "STRA8–RB interaction is required for timely entry of meiosis in mouse female germ cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    16. Hailyn V. Nielsen & Letitia Yang & James L. Mueller & Alexander J. Ritter & Ryosuke Hiwa & Irina Proekt & Elze Rackaityte & Dominik Aylard & Mansi Gupta & Christopher D. Scharer & Mark S. Anderson & B, 2025. "Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    17. Xi Li & Alfonso Poire & Kang Jin Jeong & Dong Zhang & Tugba Yildiran Ozmen & Gang Chen & Chaoyang Sun & Gordon B. Mills, 2024. "C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    18. Xiaojun Ren & Jianqing Liang & Yiming Zhang & Ning Jiang & Yuhui Xu & Mengdi Qiu & Yiqin Wang & Bing Zhao & Xiaojun Chen, 2022. "Single-cell transcriptomic analysis highlights origin and pathological process of human endometrioid endometrial carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    19. Gaofei Li & Yicong Sun & Immanuel Kwok & Liting Yang & Wanying Wen & Peixian Huang & Mei Wu & Jing Li & Zhibin Huang & Zhaoyuan Liu & Shuai He & Wan Peng & Jin-Xin Bei & Florent Ginhoux & Lai Guan Ng , 2024. "Cebp1 and Cebpβ transcriptional axis controls eosinophilopoiesis in zebrafish," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    20. Adele M. Alchahin & Shenglin Mei & Ioanna Tsea & Taghreed Hirz & Youmna Kfoury & Douglas Dahl & Chin-Lee Wu & Alexander O. Subtelny & Shulin Wu & David T. Scadden & John H. Shin & Philip J. Saylor & D, 2022. "A transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58150-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.