Embryonic Durotaxis: A Mechanical Framework for Understanding Cesarean Scar Pregnancy

Cesarean scar pregnancy (CSP), a serious complication associated with the global surge in cesarean sections, has been a significant rise in prevalence. However, the pathogenic mechanisms driving CSP remain poorly understood. In this study, we employed a mouse model of uterine surgical scarring and identified a stiffness gradient from healthy to scarred uterine tissue. While durotaxis has been widely observed in various cell types, whether mammalian embryos exhibit durotaxis has remained an open question. Using custom-designed polyacrylamide hydrogels with tunable stiffness gradients, we discovered that peri-implantation stage mouse embryos and human-derived trophoblast cell spheroids consistently exhibit durotaxis. Through integrative mechanical modeling, we uncovered that the embryonic durotaxis is initiated by asymmetric adhesion forces and driven by cell blebbing induced by an internal Marangoni flow. The durotaxis of embryos display complex migration modes, including translation, swing, and rolling and uniquely characterized by periodic migration patterns synchronized with embryo cavity oscillations. Finally, inhibiting cell blebbing significantly reduces the risk of CSP in our mouse model. These findings pioneer the concept of embryonic durotaxis and establish a mechanical framework for understanding CSP development, which opens new therapeutic avenues for intervention and management of CSP.