Recombinant Humanized Type III Collagen Improves Ovarian Function via ITGA2-Mediated Mitochondrial Function Restoration in Granulosa Cells and Extracellular Matrix Remodeling

Abstract Ovarian ageing is characterized by depletion of the follicular reserve. The extracellular matrix (ECM) provides the essential microenvironmental niche for follicles, and age-related alterations in ECM composition may adversely affect follicular dynamics. However, the precise relationship between matrix components and ovarian ageing remains unclear. In this study, we first observed a marked reduction in type III collagen (Col III) as a key alteration associated with ovarian ageing. Furthermore, we discovered that as a biomaterial, recombinant humanized type III collagen (rhCol III) ameliorated ovarian function in 12-month-old natural ageing rats, evidenced by restored estrous cycles, increased ovarian index, elevated levels of Anti-Müllerian Hormone (AMH) and Estradiol (E2), and enhanced folliculogenesis. Notably, rhCol III promoted the reorganization of the disorganized ovarian ECM into a highly ordered and dense structure, providing a supportive biological scaffold for follicular development. Additionally, supplementation of rhCol III could mitigate oxidative stress and mitochondrial dysfunction in age granulosa cells (GCs), thereby preventing apoptosis and cellular senescence. Mechanistically, rhCol III bound to the integrin α2 (ITGA2) receptor on GCs and activated the PI3K/Akt signaling pathway. Our findings highlight Col III deficiency as a critical factor in ovarian ageing and demonstrate that rhCol III supplementation rejuvenates the ovarian microenvironment via the ITGA2-PI3K/Akt axis, presenting a novel therapeutic strategy. Then ITGA2 may represent a promising target for mitigating ovarian ageing.