Age-dependent dysregulated post-ovulatory debris clearance promotes ovarian fibroinflammation
- 1Northwestern University Feinberg School of Medicine
Abstract
The ovary is one of the first organs to age, with declines in oocyte quantity and quality leading to infertility and loss of endocrine function. Why the ovary ages earlier than somatic tissues has remained enigmatic but may relate to its highly dynamic physiology and substantial demand for cellular debris clearance. Each ovulation forms a corpus luteum (CL), a transient endocrine structure which supports pregnancy but regresses in its absence. Because CLs have a short functional lifespan but prolonged structural regression, they represent a substantial source of ovarian debris. We hypothesized that post-ovulatory debris clearance becomes impaired with age and contributes to ovarian fibroinflammation. Using a CL-labeling system, we demonstrated that CLs from reproductively old mice show dysregulated regression, resulting in an accumulation of persistent CLs (pCLs) which appeared concurrently with ovarian multinucleated giant cells (MNGCs). Laser capture microdissection, RNA sequencing, and histological evaluation of CLs, 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 factors from MNGC-enriched explants 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.
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BibTeX
@misc{converse2026agedependent,
title = {{Age-dependent dysregulated post-ovulatory debris clearance promotes ovarian fibroinflammation}},
author = {A. Converse and M. J. Perry and S. S. Dipali and P. H. Hashim and J. L. Gerton and M. T. Pritchard and F. E. Duncan},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753904},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753904v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Age-dependent dysregulated post-ovulatory debris clearance promotes ovarian fibroinflammation
AU - A. Converse
AU - M. J. Perry
AU - S. S. Dipali
AU - P. H. Hashim
AU - J. L. Gerton
AU - M. T. Pritchard
AU - F. E. Duncan
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753904
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753904v1
AB - The ovary is one of the first organs to age, with declines in oocyte quantity and quality leading to infertility and loss of endocrine function. Why the ovary ages earlier than somatic tissues has remained enigmatic but may relate to its highly dynamic physiology and substantial demand for cellular debris clearance. Each ovulation forms a corpus luteum (CL), a transient endocrine structure which supports pregnancy but regresses in its absence. Because CLs have a short functional lifespan but prolonged structural regression, they represent a substantial source of ovarian debris. We hypothesized that post-ovulatory debris clearance becomes impaired with age and contributes to ovarian fibroinflammation. Using a CL-labeling system, we demonstrated that CLs from reproductively old mice show dysregulated regression, resulting in an accumulation of persistent CLs (pCLs) which appeared concurrently with ovarian multinucleated giant cells (MNGCs). Laser capture microdissection, RNA sequencing, and histological evaluation of CLs, 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 factors from MNGC-enriched explants 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.
ER -