Landry, D. A. | Search bioRxiv

bioRxiv2025

Redefining Ovarian Fibrosis Through Comparative Analysis of Collagen Architecture

Short abstractOvarian fibrosis is a known pathology of reproductive aging, becoming a growing concern for infertility and complex ovarian diseases. In research, mouse and human ovary samples are utilized, though distinct differences between species warrant validation of architectural phenotypes to accurately define its pathology. Using polarized light microscopy and orientation analysis of collagen fibers in mouse and human ovaries, we define ovarian fibrosis as the accumulation and/or anisotropic organization of fibrillar collagen within the ovarian stroma and/or cortex.

cell biology↗

bioRxiv2025

BRCA mutation alters the stromal landscape in normal ovaries

For BRCA mutation (BRCA+) carriers, the risk of ovarian cancer can be as high as 59% compared with 1.4% for the general population. While the impact of BRCA mutations on epithelial cell transformation has been extensively studied, we hypothesize that these mutations cause structural changes that prematurely transform the ovary into a rich metastatic niche that supports the early onset of ovarian cancer. Analysis of collagen content and organization in human ovaries revealed increased coherence associated with fibrosis in premenopausal BRCA+ ovaries relative to those without a BRCA mutation. Brca1 deficiency and haploinsufficiency in murine ovarian fibroblasts triggered the expression of hallmarks of senescence, including Cdkn2a (p16) and acidic {beta}-galactosidase activity. Brca1-deficient fibroblasts also acquired an antigen-presenting myofibroblastic phenotype, characterized by expression of MHC-II molecules, -SMA and extracellular matrix components, suggesting the capacity to modulate immune activity and drive structural changes resembling fibrosis. These results provide insight into the mechanisms contributing to accelerated ovarian aging in BRCA+ carriers. TeaserBRCA mutation promotes fibroblast hyperactivity and senescence that changes the stromal architecture of the ovarian niche.

molecular biology↗