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Distinctive molecular features of regenerative stem cells in the damaged male germline

Author

Listed:
  • Hue M. La

    (Centre for Reproductive Health, Hudson Institute of Medical Research
    Monash University
    Monash University)

  • Jinyue Liao

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Julien M. D. Legrand

    (Centre for Reproductive Health, Hudson Institute of Medical Research
    Monash University
    Monash University)

  • Fernando J. Rossello

    (Monash University
    University of Melbourne)

  • Ai-Leen Chan

    (Centre for Reproductive Health, Hudson Institute of Medical Research
    Monash University
    Monash University)

  • Vijesh Vaghjiani

    (Monash University
    Centre for Cancer Research, Hudson Institute of Medical Research)

  • Jason E. Cain

    (Monash University
    Centre for Cancer Research, Hudson Institute of Medical Research)

  • Antonella Papa

    (Monash University)

  • Tin Lap Lee

    (The Chinese University of Hong Kong)

  • Robin M. Hobbs

    (Centre for Reproductive Health, Hudson Institute of Medical Research
    Monash University
    Monash University)

Abstract

Maintenance of male fertility requires spermatogonial stem cells (SSCs) that self-renew and generate differentiating germ cells for production of spermatozoa. Germline cells are sensitive to genotoxic drugs and patients receiving chemotherapy can become infertile. SSCs surviving treatment mediate germline recovery but pathways driving SSC regenerative responses remain poorly understood. Using models of chemotherapy-induced germline damage and recovery, here we identify unique molecular features of regenerative SSCs and characterise changes in composition of the undifferentiated spermatogonial pool during germline recovery by single-cell analysis. Increased mitotic activity of SSCs mediating regeneration is accompanied by alterations in growth factor signalling including PI3K/AKT and mTORC1 pathways. While sustained mTORC1 signalling is detrimental for SSC maintenance, transient mTORC1 activation is critical for the regenerative response. Concerted inhibition of growth factor signalling disrupts core features of the regenerative state and limits germline recovery. We also demonstrate that the FOXM1 transcription factor is a target of growth factor signalling in undifferentiated spermatogonia and provide evidence for a role in regeneration. Our data confirm dynamic changes in SSC functional properties following damage and support an essential role for microenvironmental growth factors in promoting a regenerative state.

Suggested Citation

  • Hue M. La & Jinyue Liao & Julien M. D. Legrand & Fernando J. Rossello & Ai-Leen Chan & Vijesh Vaghjiani & Jason E. Cain & Antonella Papa & Tin Lap Lee & Robin M. Hobbs, 2022. "Distinctive molecular features of regenerative stem cells in the damaged male germline," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30130-z
    DOI: 10.1038/s41467-022-30130-z
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    References listed on IDEAS

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    1. Yan Li & Chen Xu & Bing Wang & Fujiang Xu & Fahan Ma & Yuanyuan Qu & Dongxian Jiang & Kai Li & Jinwen Feng & Sha Tian & Xiaohui Wu & Yunzhi Wang & Yang Liu & Zhaoyu Qin & Yalan Liu & Jing Qin & Qi Son, 2022. "Proteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies," Nature Communications, Nature, vol. 13(1), pages 1-26, December.

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