Aquaporin-4 participates in the migration of retinal Müller cells by facilitating water transport and cytoskeleton reorganization.

Müller cells are essential for retinal integrity and respond to injury by activating cell proliferation, migration and differentiation into a neuronal-like phenotype for tissue remodeling. Aquaporin-4 (AQP4), the most abundant water channel of the retina, contributes to water transport and the proliferation of Müller cells, but its role in the migration of these cells remains poorly understood. Because cell migration requires localized volume changes and cytoskeletal remodeling, and AQP4 has been linked to cytoskeleton dynamics, we investigated the contribution of AQP4 to Müller cell migration. MIO-M1 migrating Müller cells were exposed to TGN-020 (TGN, AQP4 inhibitor) or vehicle and we evaluated: cell migration (wound healing), AQP4, Actin and Vimentin (immunocytochemistry) and the kinetics of cell volume (videomicroscopy). Our results show that AQP4 inhibition decreased cell migration and water transport in the lamellipodia of Müller cells exposed to hypertonic media, without affecting cell volume regulation. In migrating cells, TGN also reduced the anisotropy of F-Actin fibers, which indicates their degree of organization, and changed Vimentin localization closer to the plasma membrane. Finally, the activation of the PI3K pathway regulates AQP4 expression in migrating cells. These findings identify, for the first time, a critical role of AQP4 in the migration of Müller cells, not only facilitating volume changes for lamellipodia formation but also the remodeling of the Actin and Vimentin cytoskeleton. Our results suggest the possibility of targeting AQP4 expression and/or function as a novel therapeutic strategy to prevent glial scar formation.