Hic-5 drives epithelial mechanotransduction promoting a feed-forward cycle of bronchoconstriction

TL;DR

This study shows that Hic-5, a protein in airway cells, plays a key role in converting mechanical forces into biological signals, worsening asthma by promoting a cycle of bronchoconstriction.

Contribution

The study identifies Hic-5 as a novel regulator of epithelial mechanotransduction in asthma.

Findings

Hic-5 expression increases in airway basal cells under mechanical compression.

Hic-5 knockdown reduces mechanoresponses like stress fiber formation and ET-1 secretion.

Hic-5 promotes a feed-forward cycle of bronchoconstriction via endothelin-1.

Abstract

Mechanical forces are essential for organ function, but excessive or dysregulated forces can promote pathologic conditions. In asthma, bronchoconstriction narrows the airway, compressing the airway epithelium and activating mechanotransduction, yet key regulators of mechanotransduction remain unclear. Here we show that Hic-5, a focal adhesion adaptor, is a key regulator of epithelial mechanotransduction. In human airway epithelial cells at air–liquid interface exposed to mechanical compression that mimics bronchoconstriction, we find that compression induces Hic-5 expression in airway basal cells. We further validated these in vitro findings by reanalyzing single-cell RNA-seq data from patients with asthma undergoing bronchoconstriction after allergen challenge, which revealed increased Hic-5 expression in airway basal cells. Hic-5 knockdown in human airway epithelial cells markedly attenuates mechanoresponses to compression, including stress fiber formation, differential gene expression, and increased secretion of endothelin-1 (ET-1). Through secretion of ET-1, a potent bronchoconstrictor, Hic-5 drives epithelial mechanotransduction and promotes a feed-forward cycle of bronchoconstriction, thereby highlighting dysregulated mechanical forces as active drivers of human disease.

Hic-5 drives epithelial mechanotransduction linking bronchoconstriction to asthma pathogenesis and reinforces a feed-forward bronchoconstriction loop through endothelin-1, thereby establishing dysregulated mechanical forces as active drivers of disease

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