Piezo1-expressing vocal fold epithelia modulate remodeling via effects on self-renewal and cytokeratin differentiation

Abstract

Mechanoreceptors are implicated as functional afferents within mucosa of the airways and the recent discovery of mechanosensitive channels Piezo1 and Piezo2 has proved essential for cells of various mechanically sensitive tissues. However, the role for Piezo1/2 in vocal fold (VF) mucosal epithelia, a cell that withstands excessive biomechanical insult, remains unknown. The purpose of this study was to test the hypothesis that Piezo1 is required for VF mucosal repair pathways of epithelial cell injury. Utilizing a sonic hedgehog (shh) Cre line for epithelial-specific ablation of Piezo1/2 mechanoreceptors, we investigated 6wk adult VF mucosa following naphthalene exposure for repair strategies at 1, 3, 7 and 14 days post-injury (dpi). PIEZO1 localized to differentiated apical epithelia and was paramount for epithelial remodeling events. Injury to wildtype epithelium was most appreciated at 3 dpi. Shhcre/+; Piezo1loxP/loxP, Piezo2 loxP/+ mutant epithelium exhibited severe cell/nuclear defects compared to injured controls. Conditional ablation of Piezo1 and/or Piezo2 to uninjured VF epithelium did not result in abnormal phenotypes across P0, P15 and 6wk postnatal stages compared to heterozygote and control tissue. Results demonstrate a role for Piezo1-expressing VF epithelia in regulating self-renewal via effects on p63 transcription and YAP subcellular translocation—altering cytokeratin differentiation.

PIEZO1-Mediated Mechanotransduction Regulates Collagen Synthesis on Nanostructured 2D and 3D Models of Fibrosis

“…Our results also revealed that PIEZO1 activation induces YAP accumulation in the cytoplasm, resulting in reduced YAP activity. Multiple studies have shown interactions between these pathways and their functional implications in cellular processes in other tissues/cells [41, 71-75]. Xiong et al [71] demonstrated that PIEZO1 activation promotes ovarian cancer metastasis via the Hippo/YAP signaling axis.…”

“…Recent research findings have indicated that the absence of PIEZO1 causes YAP to be excluded from the nucleus in human neural stem cells [41] and during zebrafish outflow tract valve development [73], implying that PIEZO1 may function upstream of YAP. PIEZO1 and PIEZO2 have also been identified as upstream regulators of signal transduction pathways that activate YAP for stem cell differentiation [74], also in regulating self-renewal of vocal fold mucosal epithelia [75].…”