Extracellular matrix composition and stiffness regulates progesterone responsiveness and decidualization.

Endometrial disorders impact the uterine lining and can promote ectopic endometrial tissue growth. A key feature of endometrial disorders is unresponsiveness to hormonal treatments due to progesterone resistance. Because endometrial 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 stable differentiation. Stiff matrices override these ECM cues and inhibit decidualization across ligands. Furthermore, these findings mirror activity in endometriotic lesions, with lesions across the stiffest sites displaying greater fibronectin expression and lower decidualization. Altogether, these data demonstrate a role for the lesion microenvironment in the mechanism of inhibited decidualization and progesterone responses.