Magnetically guided neurite outgrowth modulated by PIEZO1 in hiPSC-derived retinal ganglion cells

Abstract

Retinal ganglion cell (RGC) axon degeneration is one of the major causes of vision loss in glaucoma, where regeneration remains limited by the central nervous system's low intrinsic repair capacity. We applied a magnetic-guided nanotechnology approach to modulate axon growth in human-induced pluripotent stem cell-derived RGCs (hiPSC-RGCs). Magnetic Neural Axon Vectors (MagNAVs)—multi granular Fe3O4 nanoparticles functionalized with rhodamine—were efficiently internalized and directed by an external magnetic field (MF), enhancing neurite elongation and alignment. The mechanosensitive ion channel PIEZO1 was expressed in both soma and neurites. Specifically, PIEZO1 inhibition by Dooku1 enhanced neurite elongation, and activation by Yoda1 elevated somatic calcium transients without affecting neurite outgrowth. Furthermore, two-photon calcium imaging revealed that somatic calcium activity was PIEZO1-dependent, whereas neuritic calcium signaling was more responsive to magnetic force. These results indicate that PIEZO1-mediated calcium influx may negatively regulate force-induced neurite elongation. This work demonstrates a nanomaterial-based strategy for targeted axon regeneration and highlights the mechanoregulatory role of PIEZO1.