https://orcid.org/0000-0001-9408-9496
Abstract
We aimed to elucidate the function of the mechanosensitive ion channel PIEZO1 in intestinal fibrosis, which is invariably associated with Crohn’s disease (CD) and often results in strictures and obstructions, requiring surgical intervention. Notably, PIEZO1 is strongly expressed in fibrotic tissues and linked with fibrotic progression.
Intestinal tissues were procured from 28 patients diagnosed with CD and 8 healthy control subjects. Histological and immunofluorescence assays verified that PIEZO1 is substantially overexpressed in fibrotic intestinal tissues and is involved in epithelial‒mesenchymal transition (EMT). Further gene knockout experiments and transcriptome sequencing elucidated the specific role of PIEZO1 in the pathogenesis of intestinal fibrosis in CD. We generated mice with Piezo1 deletion specifically in intestinal epithelial cells (Piezo1f/f Vilcre) to validate in vivo that inhibiting Piezo1 function attenuates or reverses intestinal fibrosis associated with CD.
PIEZO1 expression was strongly increased in the fibrotic small intestine of CD patients, thereby promoting EMT and exacerbating intestinal fibrosis. In vivo investigations revealed that the conditional suppression of Piezo1 in intestinal epithelial cells significantly mitigated intestinal fibrosis in dextran sulphate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced chronic colitis model mice. In vitro examinations revealed that Piezo1 expression in intestinal epithelial cells preserved the stability of HIF-1α, induced EMT to stimulate the expression of fibrosis-associated molecules, and promoted fibrosis.
PIEZO1 plays a pivotal role in the regulation of intestinal fibrosis by maintaining the levels of HIF-1α, thereby promoting EMT. Therapeutic strategies targeting PIEZO1 could be used to prevent intestinal fibrosis in CD patients.
Lay Summary
PIEZO1 expression is up-regulated in intestinal tissues with fibrous stenosis. PIEZO1 induces epithelial mesenchymal transition and promotes fibrosis by maintaining the stability of hypoxia-inducible factor 1α. Knockdown of Piezo1 in mouse intestinal epithelial cells effectively reversed intestinal fibrosis.
