Activated dormant stem cells recover spermatogenesis in chemoradiotherapy-induced infertility

Male infertility is a recognized side effect of chemoradiotherapy. Extant spermatogonial stem cells (SSCs) may act as originators for any subsequent recovery. However, which type of SSCs, the mechanism by which they survive and resist toxicity, and how they act to restart spermatogenesis remain largely unknown. Here, we identify a small population of Set domain-containing protein 4 (Setd4)-expressing SSCs that occur in a relatively dormant state in the mouse seminiferous tubule. Extant beyond high-dose chemoradiotherapy, these cells then activate to recover spermatogenesis. Recovery fails when Setd4+ SSCs are deleted. Confirmed to be of fetal origin, these Setd4+ SSCs are shown to facilitate early testicular development and also contribute to steady-state spermatogenesis in adulthood. Upon activation, chromatin remodeling increases their genome-wide accessibility, enabling Notch1 and Aurora activation with corresponding silencing of p21 and p53. Here, Setd4+ SSCs are presented as the originators of both testicular development and spermatogenesis recovery in chemoradiotherapy-induced infertility. [Display omitted] •Setd4 marks a small subset of dormant SSCs in mouse seminiferous tubules•Dormant SSCs are able to survive high-dose chemoradiotherapy and recover spermatogenesis•Dormancy and activation of SSCs are regulated by chromatin remodeling Yang et al. report a subset of dormant spermatogonial stem cells in mouse seminiferous tubules marked by Setd4 that can survive high-dose chemoradiotherapy and recover spermatogenesis when activated. Upon activation, chromatin remodeling increases their genome-wide accessibility in which the expression of proliferation-related genes is upregulated.