Remote Activation of Wnt Signaling and Cell Proliferation by E-cadherin Magnetomechanical Stimulation

Abstract

The ability to remotely and precisely manipulate intracellular signaling pathways is a powerful tool for both fundamental biological research and therapeutic applications. Among these pathways, the Wnt/{beta}-catenin signaling cascade plays a central role in regulating cell proliferation, differentiation, and tissue regeneration. However, current methods for activating this pathway such as pharmacological agents lack spatiotemporal control and may induce severe off-target effects. In this study, we introduce a pioneering magnetogenetic toolkit to modulate the Wnt/{beta}-catenin pathway through magnetomechanical stimulation of E-cadherin, a key cell adhesion molecule intimately linked to {beta}-catenin dynamics. Engineered magnetic nanoparticles (MNPs) functionalized with the extracellular domain of E-cadherin (MNPs@E/EC15) are used to selectively bind cellular E-cadherins. By applying a weak intensity and low-gradient magnetic field using a custom-designed magnetic stimulator, localized mechanical forces sufficient to trigger E-cadherin-mediated mechanotransduction are produced. This stimulation leads to {beta}-catenin release from the membrane, nuclear translocation, and activation of Wnt target gene expression, as confirmed by transcriptomic profiling and a Wnt-responsive luciferase reporter assay. These molecular changes are also translated into functional outcomes, including enhanced cell proliferation and accelerated wound closure. This work establishes an innovative non-invasive tool for probing E-cadherin mechanobiology and remotely modulating Wnt/{beta}-catenin signaling with high spatiotemporal resolution. Unlike other tools to probe mechanotransduction, this approach enables the simultaneous modulation of many cells with precise control, using low intensity magnetic field that could be potentially translated into in vivo designs. Our findings open promising avenues for studying mechanotransduction and developing targeted regenerative therapies based on mechanical stimulation.