PRMT5 inhibition promotes cross-species spermatogonia expansion and suppresses differentiation

AI Summary

PRMT5 inhibition with EPZ015666 suppresses mouse SSC differentiation and enhances proliferation in GDNF-deficient, differentiation-prone in vitro conditions.
EPZ015666-treated SSCs retain spermatogonial identity and restore normal spermatogenesis after compound withdrawal, confirming reversible differentiation inhibition.
EPZ015666 similarly inhibits differentiation and promotes proliferation of human and non-human primate spermatogonia by blocking PRMT5 enzymatic active site.

Cell Regen. 2026 Jul 7;15(1):22. doi: 10.1186/s13619-026-00293-x.

ABSTRACT

Spermatogonial stem cells (SSCs) hold great promise for treating male infertility, but their clinical translation is impeded by the lack of optimal conditions to maintain their undifferentiated state in vitro. In this study, we focused on epigenetic regulators upregulated during differentiation as potential targets. Through a small-molecule screen targeting such conserved regulators, we found that PRMT5 inhibition suppressed mouse SSC differentiation and enhanced their proliferation in a GDNF-deficient, differentiation-prone microenvironment in vitro. Using SSC transplantation assays, we confirmed that EPZ015666-treated SSCs retained their spermatogonial identity. This differentiation-inhibitory effect was reversible upon EPZ015666 withdrawal, allowing restoration of normal spermatogenesis. Notably, EPZ015666 also inhibited differentiation and promoted the proliferation of human and non-human primate spermatogonia in vitro. Mechanistically, EPZ015666 exerted this effect by inhibiting the enzymatic active site of PRMT5. These findings suggest that PRMT5 inhibition could provide a novel strategy for culturing human SSCs in vitro.

PMID:42410128 | DOI:10.1186/s13619-026-00293-x

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