TRPV4 regulates matrix stiffness and TGFβ1‐induced epithelial‐mesenchymal transition

Abstract

Substrate stiffness (or rigidity) of the extracellular matrix has important functions in numerous pathophysiological processes including fibrosis. Emerging data support a role for both a mechanical signal, for example, matrix stiffness, and a biochemical signal, for example, transforming growth factor β1 (TGFβ1), in epithelial‐mesenchymal transition (EMT), a process critically involved in fibrosis. Here, we report evidence showing that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive channel, is the likely mediator of EMT in response to both TGFβ1 and matrix stiffness. Specifically, we found that: (a) genetic ablation or pharmacological inhibition of TRPV4 blocked matrix stiffness and TGFβ1‐induced EMT in normal mouse primary epidermal keratinocytes (NMEKs) as determined by changes in morphology, adhesion, migration and alterations of expression of EMT markers including E‐cadherin, N‐cadherin (NCAD) and α‐smooth muscle actin (α‐SMA), and (b) TRPV4 deficiency prevented matrix stiffness‐induced EMT in NMEKs over a pathophysiological range. Intriguingly, TRPV4 deletion in mice suppressed expression of mesenchymal markers, NCAD and α‐SMA, in a bleomycin‐induced murine skin fibrosis model. Mechanistically, we found that: (a) TRPV4 was essential for the nuclear translocation of YAP/TAZ (yes‐associated protein/transcriptional coactivator with PDZ‐binding motif) in response to matrix stiffness and TGFβ1, (b) TRPV4 deletion inhibited both matrix stiffness‐ and TGFβ1‐induced expression of YAP/TAZ proteins and (c) TRPV4 deletion abrogated both matrix stiffness‐ and TGFβ1‐induced activation of AKT, but not Smad2/3, suggesting a mechanism by which TRPV4 activity regulates EMT in NMEKs. Altogether, these data identify a novel role for TRPV4 in regulating EMT.

Ablation of TRPV4 in HepG2 with Its CRISPR/Cas9 Enhances Its Wound Healing

“…Thus, we rationalize that the "gain of function" of mutant TRPV4 can be cured by the genetic scissor to remove the point mutant TRPV4 which caused each specific human genetic disease. Therefore, to remove TRPV4 genome, we design the specific TRPV4 genetic scissor with the several guide RNA expression vector (Figure 1(b) [32]. This study also supports a role for TRPV4 in metastasis by regulating cancer cell stiffness and cytoskeleton at the cell cortex.…”

TRPV4—A Missing Link Between Mechanosensation and Immunity

“…Finally, substrate stiffness is regulated by the composition of the ECM which changes as a function of physiological (development, aging) and pathophysiological (atherosclerosis, hypertension, fibrosis) processes (90)(91)(92)(93). TRPV4 has been identified as a major mechanosensor for substrate stiffness, but so far this function has been exclusively attributed to parenchymal cells (30,31,(94)(95)(96)). Yet, it is fair to speculate that changes in substrate stiffness will similarly affect the mechanical forces that act upon immune cells during the processes of adhesion and transmigration, which accordingly may affect TRPV4-dependent cellular responses.…”

Dysfunctional Mechanotransduction through the YAP/TAZ/Hippo Pathway as a Feature of Chronic Disease

“…As mice with ablated TRPV4 or TREK genes show reduced and increased sensitivity to mechanical stress, respectively [120,121], these channels may act in opposition to regulate homeostatic responses to mechanical stress in the retina. Interestingly, TRPV4 activation causes YAP/TAZ nuclear translocation during cellular epithelial-mesenchymal transition (EMT) in keratinocytes [122,123]. It will be useful to identify if TRPV4 also effects this process in retinal ganglion cells.…”