IL1R2 Marks and Sorts a Spermatogonial Stem Cell Population Critical for Restoring Spermatogenesis Upon Interruption in Mammals

ABSTRACT Self‐renewal and differentiation of spermatogonial stem cells (SSCs) are critical for sustaining spermatogenesis in adult mammals. However, SSCs are highly heterogeneous, comprising a complex array of subpopulations whose identities and dynamic transitions remain greatly underappreciated. Through in silico analysis, we identified IL1R2 as a surface marker specific to the SSC subpopulation. IL1R2 enables the specific sorting of functionally active SSCs in both human and mouse. Il1r2 ^CreERT2/+ Rosa26 ^mTmG/+ mice allowed us to pulse‐label and trace the lineage of Il1r2 ‐expressing cells. We confirmed that IL1R2 ⁺ SSCs support spermatogenesis via both self‐renewal and differentiation. Following spermatogenic disruption, IL1R2 ⁺ SSCs are reactivated for proliferation via the PI3K‐AKT‐mTORC1 pathway to replenish the SSC pool. Importantly, we demonstrated that PI3K‐AKT‐mTORC1 agonists can effectively enhance the recovery of spermatogenesis upon disruption. These findings highlight a promising therapeutic strategy to mitigate chemotherapy‐induced infertility.