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

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 () and Robin M. Hobbs ()
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Hue M. La: Centre for Reproductive Health, Hudson Institute of Medical Research
Jinyue Liao: The Chinese University of Hong Kong
Julien M. D. Legrand: Centre for Reproductive Health, Hudson Institute of Medical Research
Fernando J. Rossello: Monash University
Ai-Leen Chan: Centre for Reproductive Health, Hudson Institute of Medical Research
Vijesh Vaghjiani: Monash University
Jason E. Cain: Monash University
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

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30130-z

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