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

## TL;DR

This study identifies IL1R2 as a marker for spermatogonial stem cells that can restore sperm production after disruption, offering a potential therapy for infertility.

## Contribution

The discovery of IL1R2 as a specific marker for functionally active spermatogonial stem cells in both mice and humans.

## Key findings

- IL1R2 marks a subpopulation of spermatogonial stem cells critical for restoring spermatogenesis.
- IL1R2+ stem cells proliferate via the PI3K-AKT-mTORC1 pathway after spermatogenic disruption.
- PI3K-AKT-mTORC1 agonists enhance recovery of spermatogenesis following disruption.

## 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.

Spermatogonial stem cells (SSCs) provide critical support to spermatogenesis. Here, the author established Il1r2 as a sorting marker for SSCs, with which further insights into the SSC heterogeneity and dynamic features can be obtained. They also confirmed findings in both mouse and human, thus validating IL1R2 as the surface marker for isolating and characterizing SSCs. Furthermore, they discovered that IL1R2+ SSCs can be reactive in proliferation and contribute to restoring SSCs homeostasis upon disruption, which requires the activation of the PI3K‐AKT‐mTORC1 pathway. More importantly, they confirmed that this process can be effectively enhanced by agonist of the pathway. Overall, their findings not only provide new insights into the complexity of SSCs but also propose a promising route for isolating and preserving SSCs for therapeutic purposes.