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

• Published in: Nature communications 2022-05, Vol.13 (1), p.2500-2500, Article 2500
• Main Authors: La, Hue M., Liao, Jinyue, Legrand, Julien M. D., Rossello, Fernando J., Chan, Ai-Leen, Vaghjiani, Vijesh, Cain, Jason E., Papa, Antonella, Lee, Tin Lap, Hobbs, Robin M.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/106; 14; 45; 45/91; 631/136/2434/1822; 631/532/2118; 631/532/489; 631/80/86/2368; 64/60; 82/51; 82/80; 96/100; 96/31; 96/95; AKT protein; Cell differentiation; Cell Differentiation - physiology; Chemotherapy; Damage; Fertility; Genotoxicity; Germ cells; Growth factors; Humanities and Social Sciences; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Maintenance; Male; Males; Mechanistic Target of Rapamycin Complex 1 - metabolism; multidisciplinary; Phosphatidylinositol 3-Kinases - metabolism; Recovery; Regeneration; Science; Science (multidisciplinary); Signal transduction; Signaling; Spermatogenesis - genetics; Spermatogonia; Spermatozoa; Stem cells; Stem Cells - metabolism; Testis - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-30130-z

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. Male germline regeneration after damage is dependent on spermatogonial stem cells (SSCs) but pathways mediating the regenerative response are unclear. Here the authors define roles for growth factor signalling and mTORC1 in SSC-driven regeneration.