The role of biomechanical tissue properties in maintaining gonadal tissue function during aging is increasingly recognized. In testis, previous work has shown that the biomechanical properties of the tissue environment determine Leydig cell differentiation and hormone production, but this process remains to be fully understood mechanistically. In a study in Cell Reports, Jiayu Huang, Lu Sun, Yuehan Yin, Huan Yang and colleagues now show that extracellular matrix stiffness increases in aging mouse testes; this promotes PIEZO1-mediated Ca2+ influx, mitochondrial dysfunction and reactive oxygen species (ROS) production, which impairs stem Leydig cell (SLC) homeostasis.
In mice aged 2 months, 12 months, and 24 months old, the researchers detected gradually increasing testicular tissue stiffness using atomic force microscopy. These results correlated with transcriptomic data that indicated decreased proliferation and differentiation of SLCs with age. Indeed, when explanting SLCs from aged mice onto soft 2D gels, cell proliferation was enhanced. To understand the underlying mechanisms, the authors cultured SLCs on stiff gels and inhibited mechanosensitive signal transduction via a PIEZO1 inhibitor. This treatment improved differentiation, increased testosterone production and limited Ca2+ influx. The researchers further showed that in cells cultured on stiff gels, mitochondrial function was impaired and mitochondrial ROS production was enhanced. Applying the ROS scavenging molecule NAC (N-acetylcysteine) improved mitochondrial function and cell proliferation, as well as differentiation on stiff gels. The team then tested these mechanisms in a 3D environment and found that, similar to the 2D gels, stiffness reduced testosterone production, which was accompanied by increased Ca2+ influx and diminished mitochondrial function.
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