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<p>Spermatogonial stem cells (SSCs)&#xa0;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.</p>

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PRMT5 inhibition promotes cross-species spermatogonia expansion and suppresses differentiation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月7日

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  • Zhaokai Yao,
  • Wen Wang,
  • Kang Tang,
  • Yuning Yang,
  • Shaofang Ren,
  • Yetian Weng,
  • Linzi Ma,
  • Dingyao Chen,
  • Haoxu Gu,
  • Jialin Wan,
  • Zhaoting Liu,
  • Yi Zheng,
  • Chaohui Li,
  • Fang Luo,
  • Xiao-Yang Zhao,
  • Yong Fan

摘要

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.