Piezo1 in intestinal epithelial cells plays a critical role in the mechanobiological positive feedback underlying intestinal fibrosis.

BACKGROUND AND AIMS: Intestinal fibrosis involves extracellular matrix stiffening. Piezo1, a mechanosensitive ion channel highly expressed in intestinal epithelial cells (IECs), may sense this change. We investigated whether IEC Piezo1 drives fibrosis and explored the underlying mechanobiological mechanism.

METHODS

Dextran sulfate sodium (DSS)-induced fibrosis models, inflammatory bowel disease (IBD) patient samples, and IEC-specific Piezo1 knockout (Piezo1ΔIEC) mice were used. RNA-sequencing, Seahorse assays, and stiffness-gradient hydrogels (1-10 kPa) were applied to assess Piezo1 function, oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS), epithelial-mesenchymal transition (EMT) of IECs, and the anti-fibrosis effect of vitamin C.

RESULTS

Piezo1 expression was significantly upregulated in IECs from fibrotic regions of both DSS model mice and IBD patients. IEC Piezo1 deficiency alleviated DSS-induced intestinal fibrosis without substantially altering chronic inflammation or fibroblast activation/proliferation. Piezo1 deficiency suppressed the partial EMT phenotype in IECs, as evidenced by preserved E-cadherin and Claudin-1 expression. RNA-sequencing and functional assays revealed enhanced OXPHOS activity in Piezo1-deficient IECs. In vitro, matrix stiffness of 4 kPa (mimicking fibrotic tissue) activated Piezo1, increased intracellular Ca2+ and ROS accumulation, and induced EMT. Knockout of Piezo1 or treatment with vitamin C prevented these stiffness-induced changes. Oral administration of high-dose vitamin C in vivo reduced intestinal fibrosis and suppressed IEC EMT.

CONCLUSIONS

Piezo1 plays a critical role in the sensing of pathological extracellular matrix stiffness in intestinal fibrosis, driving an ROS-EMT axis that promotes disease progression. Targeting Piezo1 or its downstream ROS pathway, for instance with vitamin C, represents a potential therapeutic strategy for intestinal fibrosis.