High matrix stiffness triggers testosterone decline inaging males by disrupting stem Leydig cell poolhomeostasis by Jiayu Huang & Lu Sun & Yuehan Yin & Huan Yang & Kaixuan Zeng & Peng Huang & Xiaomei Liang & Jiahong Wu & Andy Peng Xiang & Jiancheng Wang instant download

High matrix stiffness triggers testosterone decline inaging males by disrupting stem Leydig cell poolhomeostasis by Jiayu Huang & Lu Sun & Yuehan Yin & Huan Yang & Kaixuan Zeng & Peng Huang & Xiaomei Liang & Jiahong Wu & Andy Peng Xiang & Jiancheng Wang instant download

SUMMARYAging is closely related to the decline of male reproductive endocrine function, which is manifested as insufficient testosterone production. It is well known that stem cell pool stability is crucial for maintaining tissuefunction. However, the relationship between aging and the stem Leydig cell (SLC) pool homeostasis remainsunclear. Here, we demonstrate that extracellular matrix (ECM) stiffness increases in aging testes, and SLCpool homeostasis is imbalanced. Mechanistically, high ECM stiffness increases calcium influx mediatedby Piezo1, leading to mitochondrial dysfunction and excessive reactive oxygen species (ROS). ExcessiveROS promotes Gli1 degradation via the ubiquitin-proteasome pathway, ultimately inhibiting the proliferationand differentiation ability of SLCs. Together, these findings reveal the role of ECM stiffness, a biomechanicalproperty in testes, in regulating SLC pool homeostasis and suggest that pretreatment of SLCs with low ECMstiffness in vitro may be an effective strategy for their expansion and for restoring testosterone levels in agingmales.