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-κB 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. 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.

瘢痕形成是成人伤口修复的标志性特征，可长期损害组织结构与功能。为阐明这一普遍生物学现象，我们旨在探究由常见且标准化的外科手术——剖宫产术后子宫瘢痕所引发的瘢痕相关组织稳态失衡。深部子宫瘢痕与孕妇群体中发病率快速攀升的胎盘植入谱系（placenta accreta spectrum, PAS）密切相关，该疾病以侵袭性滋养细胞侵袭子宫为核心特征，常需在分娩时实施子宫切除术。我们成功构建了子宫瘢痕模型，该模型可重现PAS样侵袭表型；研究发现，瘢痕基质通过糖酵解供能的细胞收缩激活机械敏感性离子通道（mechanosensitive ion channel）Piezo1。Piezo1的激活可升高细胞内钙活性并诱导蛋白激酶C（Protein kinase C）活化，进而介导NF-κB核转位及MafG蛋白稳定化。蜕膜的此类炎性转化可促进白细胞介素8（IL-8）与粒细胞集落刺激因子（G-CSF）的合成与分泌，通过趋化作用招募侵袭性滋养细胞向瘢痕部位聚集，从而启动PAS的发生进程。本研究证实，瘢痕的异常力学特性会干扰胎盘形成过程中的基质-上皮稳态，该发现对肿瘤转移（cancer dissemination）的相关研究亦具有借鉴意义。我们针对瘢痕部位存在的异常机械信号是否会将蜕膜成纤维细胞转化为更易被绒毛外滋养细胞（extravillous trophoblast, EVT）侵袭的状态这一科学问题展开研究，构建了蜕膜瘢痕样模型（Scar）及其生理对照模型（Physio）。为深入解析导致EVT异常侵袭的潜在分子机制，我们分别从生理对照组与瘢痕模型组的蜕膜基质成纤维细胞（decidual stromal fibroblasts, dESFs）中提取总RNA进行测序，并开展基因表达谱分析。