Embryonic Durotaxis: A Mechanical Framework for Understanding Cesarean Scar Pregnancy

Cesarean scar pregnancy (CSP) is an increasingly common complication associated with the rise in cesarean section rates, yet its underlying mechanisms remain poorly understood. In this study, we identified a stiffness gradient between healthy and scarred uterine tissues in both human cesarean samples and mouse uterine scar models. By employing gradient stiffness hydrogels, we demonstrated that mouse embryos and human trophoblast spheroids exhibit durotaxis, migrating preferentially toward stiffer areas. This migration occurs through three-dimensional complex behaviors--translation, swinging, and rolling--characterized by periodic patterns that align with cavity oscillations. Embryonic durotaxis is initiated from asymmetric adhesion forces and is driven by embryonic protrusive forces, generated from Marangoni-like tissue flows. The intrinsic cavity oscillations further amplify and sustain embryonic durotaxis. Finally, pharmacological inhibition of embryonic durotaxis significantly reduced CSP incidence in the mouse model. Our findings establish the concept of embryonic durotaxis, which may provide novel therapeutic avenues for CSP prevention.