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Published on: October 24, 2025
Ovarian Extracellular Matrix Mechanics Regulate Oocyte-Follicle Interactions During Female Reproductive Aging
Xingyu Shen1, Haiyang Wang1,2, Gefei Cao1
1Mechanobiology Institute (MBI), National University of Singapore, Singapore, Singapore.
Aging Cell
|August 13, 2026
Summary
Ovarian aging increases stromal stiffness, impairing follicle function and oocyte quality. Restoring TGF-β signaling in granulosa cells can counteract these age-related fertility declines.
Area of Science:
- Reproductive Biology
- Biomedical Engineering
- Gerontology
Background:
- Female reproductive aging is characterized by ovarian functional decline and infertility.
- Changes in the ovarian extracellular matrix (ECM) during aging are implicated but poorly understood.
- The impact of ECM biophysical properties on follicle development and oocyte quality requires further investigation.
Purpose of the Study:
- To investigate age-related changes in ovarian ECM mechanics.
- To determine the effect of increased stromal stiffness on follicle growth and oocyte quality.
- To identify molecular pathways mediating the impact of ECM stiffness on ovarian aging.
Main Methods:
- Spatiotemporal analysis of ovarian ECM using mass spectrometry, immunohistochemistry, and nanoindentation.
- In vitro culture of isolated follicles in soft and stiff hydrogels mimicking young and aged ovarian stroma.
- Assessment of follicle growth, oocyte quality, granulosa cell (GC) proliferation, and transzonal projections (TZPs).
- RNA sequencing (RNA-seq) to identify affected signaling pathways and validation via Smad7 silencing.
Main Results:
- Ovarian stromal stiffness increases approximately 2.5-fold with age, while follicle stiffness remains unchanged.
- Increased stiffness significantly reduces GC proliferation, oocyte quality, and TZP-mediated GC-oocyte interactions.
- RNA-seq identified TGF-β signaling as a key pathway affected by stromal stiffness.
- Smad7 silencing, which activates TGF-β signaling, rescued TZP formation and oocyte quality in stiff matrices.
Conclusions:
- Age-related increases in ovarian stromal stiffness contribute to follicular dysfunction and reduced oocyte quality.
- TGF-β signaling is a critical mediator of the effects of ECM mechanics on ovarian aging.
- Targeting TGF-β signaling presents a potential therapeutic strategy to mitigate fertility loss associated with ovarian aging and fibrosis.
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