Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, USA.
Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA.
Nat Commun. 2024 Sep 27;15(1):8379. doi: 10.1038/s41467-024-52351-0.
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.
瘢痕组织形成是成人伤口修复的标志，可慢性影响组织结构和功能。为了了解一般现象，我们试图探讨由常见且标准化的手术（剖宫产导致的子宫瘢痕）引起的瘢痕驱动的组织平衡失调。深部子宫瘢痕与孕妇中胎盘植入谱（PAS）的一种快速增加的情况有关，其特征为侵袭性滋养细胞侵入子宫，常常需要在分娩时进行子宫切除术。我们创建了子宫瘢痕模型，模拟 PAS 样侵袭表型，表明瘢痕基质通过糖酵解驱动的细胞收缩激活机械敏感离子通道 Piezo1。Piezo1 激活增加细胞内钙活性和蛋白激酶 C 激活，导致 NF-κB 核易位和 MafG 稳定。这种蜕膜的炎症转化导致 IL-8 和 G-CSF 的产生，趋化性招募侵袭性滋养细胞向瘢痕移动，从而引发 PAS。我们的研究表明，瘢痕的异常力学扰乱了胎盘形成中的基质-上皮细胞平衡，这对癌症的扩散有影响。
