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

Wenqiang Du, Ashkan Novin, Yamin Liu, Junaid Afzal, Yasir Suhail, Shaofei Liu, Nicole R Gavin, Jennifer R. Jorgensen, Christopher M. Morosky, Reinaldo Figueroa, Tannin A. Schmidt, Melinda E. Sanders, Molly Brewer, Kshitiz Gupta
In: Nature Communications · 2024 · vol. 15(1) , pp. 8379 · doi:10.1038/s41467-024-52351-0 · PMID:39333481 · W4402922983
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Uterine scar matrix activates Piezo1 channels via cellular contraction, driving inflammation and trophoblast invasion characteristic of placenta accreta spectrum.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 ⓘ

The paper investigated how a uterine cesarean scar matrix alters decidual stromal fibroblasts to promote a placenta accreta spectrum (PAS)-like phenotype, using patient-derived tissue characterization and an in vitro scar-induced placentation/invasion model. They found that scar-matrix–imprinted mechanical cues dysregulated decidualization in endometrial stromal fibroblasts, driving Piezo1 mechanotransduction via glycolysis-fueled contraction, which increased intracellular calcium, activated PKC/NF-κB signaling, stabilized MafG, and induced IL-8 and G-CSF that enhanced extravillous trophoblast invasion toward scar. A stated caveat is that the mechanistic model depends on an in vitro recapitulation of the scar–decidua microenvironment rather than direct in vivo confirmation of the full pathway. This paper is centrally about endometriosis and/or adenomyosis — it specifically studies placenta accreta spectrum mechanisms driven by uterine scar mechanics rather than endometriosis/adenomyosis, with no explicit focus on those conditions.

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Abstract

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.

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