Scar matrix drives Piezo1 mediated stromal inflammation leading to placenta accreta spectrum

Scar tissue formation is a hallmark of wound repair in adults and can chronically affect tissue architecture and function. To understand the general phenomena, we sought to explore scar-driven imbalance in tissue homeostasis caused by a common, and standardized surgical procedure, the uterine scar due to cesarean surgery. Deep uterine scar is associated with a rapidly increasing condition in pregnant women, placenta accreta spectrum (PAS), characterized by aggressive trophoblast invasion into the uterus, frequently necessitating hysterectomy at parturition. We created a model of uterine scar, recapitulating PAS-like invasive phenotype, showing that scar matrix activates mechanosensitive ion channel, Piezo1, through glycolysis-fueled cellular contraction. Piezo1 activation increases intracellular calcium activity and Protein kinase C activation, leading to NF-?B nuclear translocation, and MafG stabilization. This inflammatory transformation of decidua leads to production of IL-8 and G-CSF, chemotactically recruiting invading trophoblasts towards scar, initiating PAS. Our study demonstrates aberrant mechanics of scar disturbs stroma-epithelia homeostasis in placentation, with implications in cancer dissemination. Overall design: We asked if the aberrant mechanical signals present at the scar transform decidual fibroblasts to be more invasable to EVT invasion, we created a scar-like model of decidua (Scar) and its physiological counterpart (Physio). To gain insight into the underlying mechanisms contributing to the aberrant EVT invasion, we isolated the RNA from dESFs on Physio and Scar for sequencing and then performed gene expression profiling analysis.