Abstract
The functional roles of bioelectrical signals (ES) created by the flow of specific ions at the mammalian lens equator are poorly understood. We detected that mature, denucleated lens fibers expressed high levels of the α1 and β1 subunits of Na+/K+‐ATPase (ATP1A1 and ATP1B1 of the sodium pump) and had a hyperpolarized membrane potential difference (Vmem). In contrast, differentiating, nucleated lens fiber cells had little ATP1A1 and ATP1B1 and a depolarized Vmem. Mimicking the natural equatorial ES with an applied electrical field (EF) induced a striking reorientation of lens epithelial cells to lie perpendicular to the direction of the EF. An EF also promoted the expression of β‐crystallin, aquaporin‐0 (AQP0) and the Beaded Filament Structural Protein 2 (BFSP2) in lens epithelial cells (LECs), all of which are hallmarks of differentiation. In addition, applied EF activated the AKT and CDC2 and inhibition of AKT reduced the activation of CDC2. Our results indicate that the endogenous bioelectrical signal at the lens equator promotes differentiation of LECs into denucleated lens fiber cells via depolarization of Vmem. Development of methods and devices of EF application or amplification in vivo may supply a novel treatment for lens diseases and even promote regeneration of a complete new lens following cataract surgery.
Highlights
The ocular lens is transparent and comprises two cell types: a monolayer of lens epithelial cells (LECs) which forms a cap at the front and the highly elongated lens fiber cells (LFCs), which differentiate from LECs at the lens equator
Throughout adult life, lens epithelial cells transdifferentiate into lens fiber cells through migration, proliferation in organized parallel arrays, elongation, and denucleation (McCaig et al, 2005)
As fiber differentiation is a major event in lens morphogenesis, much effort has been focused on determining how this is regulated
Summary
The ocular lens is transparent and comprises two cell types: a monolayer of lens epithelial cells (LECs) which forms a cap at the front and the highly elongated lens fiber cells (LFCs), which differentiate from LECs at the lens equator. A cascade of regulated proteolytic events enables the lens fiber cells to pack tightly together and the lens core to exclude water (Korlimbinis, Berry, Thibault, Schey, & Truscott, 2009; Lampi et al, 1998; Lampi, Shih, Ueda, Shearer, & David, 2002; Liu, Xu, Gu, Nicholson, & Jiang, 2011; Ueda, Duncan, & David, 2002), while fiber cells within the same growth shell fuse (Shestopalov & Bassnett, 2000, 2003) This epithelial to fiber cell differentiation process is ongoing throughout life, is promoted by the Wnt-Fz/PCP (Wnt-Frizzled/Planar Cell Polarity) signalling pathway (Chen, Stump, Lovicu, & McAvoy, 2006; Chen et al, 2009) and by a gradient of fibroblast growth factor (FGF) (Lovicu & McAvoy, 2005; Robinson, 2006; Zhao et al, 2008) and is unique to lens. We show that the extracellular ES together with the Vmem at lens equator play multiple physiological roles that regulate lens development, differentiation, and regeneration (Sundelacruz et al, 2009) and which collectively may be capable of building a lens
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