Age-dependent dysregulated post-ovulatory debris clearance promotes ovarian fibroinflammation

Laser capture microdissection, RNA sequencing, and histological evaluation of CLs, persistent (pCLs), and MNGCs demonstrated that pCLs were focal hotspots of proinflammatory and debris-associated signatures enriched in lipids, extracellular matrix, and immune cells. Although pCLs retained luteal features, they were transcriptionally more similar to MNGCs than CLs. Consistent with this, an ex vivo CL model acquired MNGC-associated molecular features during extended culture, suggesting that pCLs may represent sites of MNGC formation.

Culture of isolated follicles or ovarian stromal organoids with an MNGC-derived secretome induced compartment-specific fibroinflammatory responses. These findings provide novel mechanistic insight into ovarian aging, whereby post-ovulatory debris clearance is compromised with age, leading to pCL accumulation, MNGC formation, and a fibroinflammatory milieu.