Extracellular Matrix Composition and Stiffness Regulates Progesterone Responsiveness and Decidualization

Danielle Klunk, Laura Homewood, Daniel Abebayehu
2026 · doi:10.17632/4nrrgjc932 · W7168275397
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-07-17 ⓘ

This study found that extracellular matrix stiffness and composition, specifically laminin and fibronectin, modulate progesterone-induced decidualization in fibroblasts, with stiff matrices inhibiting differentiation and mirroring observations in fibrotic endometriosis lesions.

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⚙ AI-generated deep summary by qwen3.7-flash, 2026-10-27 · read from full text ⓘ

This study investigates how extracellular matrix composition and stiffness influence progesterone responsiveness and decidualization in healthy fibroblasts using hydrogel models. The researchers found that while specific ligands like laminin or fibronectin modulate the timing and stability of differentiation signals, stiff matrices consistently override these biochemical cues to inhibit decidualization. These experimental results align with observations in endometriotic lesions, which exhibit increased stiffness and fibronectin expression alongside reduced decidualization. This paper is centrally about endometriosis — specifically exploring how the fibrotic microenvironment contributes to progesterone resistance in endometriosis lesions.

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Abstract

Endometriosis is an inflammatory disease of endometrium found outside the uterus. Approximately a third of patients remain unresponsive to hormonal treatments due to progesterone resistance. Because endometriosis lesions are found within fibrotic extracellular matrix (ECM), we hypothesized that ECM stiffness and composition regulate progesterone responses. We used hydrogels to mimic physiological stiffnesses and examine how mechanical and biochemical ECM cues influence progesterone-induced differentiation (decidualization) in healthy fibroblasts. We determined that ECM ligands modulate decidualization, with laminin slowing secretory responses in favor of stabilizing upstream FOXO1 and WNT4 signaling, while fibronectin produces quicker but less stabilized differentiation. Stiff matrices override these ECM cues and inhibit decidualization across ligands. Furthermore, these findings mirror activity in endometriotic lesions based on lesions across stiffest sites displaying greater fibronectin expression and lower decidualization. Altogether, these data demonstrate a role for lesion microenvironment in the mechanism of inhibited decidualization and progesterone responses.
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Extracellular Matrix Composition and Stiffness Regulates Progesterone Responsiveness and Decidualization Description Endometriosis is an inflammatory disease of endometrium found outside the uterus. Approximately a third of patients remain unresponsive to hormonal treatments due to progesterone resistance. Because endometriosis lesions are found within fibrotic extracellular matrix (ECM), we hypothesized that ECM stiffness and composition regulate progesterone responses. We used hydrogels to mimic physiological stiffnesses and examine how mechanical and biochemical ECM cues influence progesterone-induced differentiation (decidualization) in healthy fibroblasts. We determined that ECM ligands modulate decidualization, with laminin slowing secretory responses in favor of stabilizing upstream FOXO1 and WNT4 signaling, while fibronectin produces quicker but less stabilized differentiation. Stiff matrices override these ECM cues and inhibit decidualization across ligands. Furthermore, these findings mirror activity in endometriotic lesions based on lesions across stiffest sites displaying greater fibronectin expression and lower decidualization. Altogether, these data demonstrate a role for lesion microenvironment in the mechanism of inhibited decidualization and progesterone responses. Files Institutions - University of VirginiaVirginia, Charlottesville

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