Transforming destructive mechanical cues into therapeutic power: Activation of PIEZO1 and TRPV4 counteracts mechano-induced damage of cellular junctions in Hailey-Hailey disease.

INTRODUCTION

Hailey-Hailey disease (HHD) is characterized by impaired intracellular calcium transport due to ATP2C1 mutations, leading to defective inter-keratinocyte adhesion and acantholysis, especially under mechanical stimulation, which exacerbates the disease. Despite the clinical consensus on the link between mechanical stimulation and HHD progression, effective therapeutic strategies targeting the mechanical aspects of the disease remain unexplored.

OBJECTIVES

The aim of this study is to introduce a novel mechanotherapeutic approach that leverages the overactivation of mechanosensitive calcium channels, transforming destructive mechanical forces into therapeutic power.

METHODS

We employed an experimental design involving ATP2C1 knockdown HaCaT cells to assess the effects of mechanical stretching on intercellular junctions. We compared the protective effects of high-calcium environments and tested specific agonists for mechanosensitive calcium channels, specifically PIEZO1 and TRPV4, to evaluate their ability to restore junction integrity under mechanical stress.

RESULTS

Our findings revealed that mechanical stretching significantly disrupted intercellular junctions in ATP2C1 knockdown HaCaT cells, while high-calcium environments offered limited protective effects. Remarkably, agonists of PIEZO1 and TRPV4 fully provided protection against barrier disruption during mechanical stress without necessitating additional calcium supplementation. This effect was not observed with non-mechanosensitive calcium channel agonists like TRPA1 and TRPV1. Additionally, atomic force microscopy and molecular analysis demonstrated that PIEZO1 and TRPV4 agonists accelerate calcium uptake during mechanical stimulation, with calcium being transported via SERCA channels to stabilize intercellular junctions.

CONCLUSION

These findings highlight a potential paradigm shift in treating blistering diseases by utilizing mechanical stimulation and mechanosensitive pathways to restore cellular function.