Extracellular Matrix Composition and Stiffness Regulates Progesterone Responsiveness and Decidualization

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.