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

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.