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

Du Wenqiang, 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 Sanders, Molly A. Brewer and Kshitiz ()
Additional contact information
Du Wenqiang: University of Connecticut Health Center
Ashkan Novin: University of Connecticut Health Center
Yamin Liu: University of Connecticut
Junaid Afzal: University of California San Francisco
Yasir Suhail: University of Connecticut Health Center
Shaofei Liu: University of Connecticut Health Center
Nicole R. Gavin: University of Connecticut Health Center
Jennifer R. Jorgensen: University of Connecticut Health Center
Christopher M. Morosky: University of Connecticut Health Center
Reinaldo Figueroa: Saint Francis Hospital and Medical Center
Tannin A. Schmidt: University of Connecticut Health Center
Melinda Sanders: University of Connecticut Health Center
Molly A. Brewer: University of Connecticut Health Center
Kshitiz: University of Connecticut Health Center

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52351-0

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