Lithium stabilizes the polarized lens epithelial phenotype and inhibits proliferation, migration, and epithelial mesenchymal transition.
Posterior capsule opacification (PCO) is a common complication of cataract surgery caused by epithelial mesenchymal transition (EMT) and aberrant lens cell growth. One path to prevention depends on maintaining the quiescent lens epithelial phenotype. Here we report that lithium chloride (LiCl) is a potent stabilizer of the lens epithelial phenotype. In lens epithelial explants (controls), at low cell density, cells readily depolarized, spread out, and proliferated. By contrast, in the presence of LiCl, cells did not spread out or exhibit migratory behaviour. Using concentrations of 1-30 mM LiCl we also showed that cell proliferation is inhibited in a dose-dependent manner. Confocal microscopy and immunohistochemistry for ZO-1 and E-cadherin showed that LiCl treatment maintained tight junctions at the apical margins of cells. Taken together with measurements of cell heights, this showed that the cells in LiCl-treated explants maintained the apical baso-lateral polarity and cobblestone-like packing that is characteristic of lens epithelial cells in vivo. Significantly, the effects of LiCl also extended to blocking the potent EMT/cataract-promoting effects of transforming growth factor beta (TGFbeta) on lens epithelial cells. In TGFbeta-treated explants, cells progressively dissociated from one another, taking on various elongated spindle shapes and strongly expressing alpha-smooth muscle actin (alpha-SMA). These features are characteristic of PCO. In both rat and human capsulorhexis explants, LiCl treatment effectively blocked the accumulation of alpha-SMA and maintained the cells in a polarized, adherent, cobblestone-packed monolayer. These findings highlight the feasibility of applying molecular strategies to stabilize lens epithelial cells and prevent aberrant differentiation and growth that leads to cataract.
Stump
R J W
RJ
Save Sight Institute, University of Sydney, NSW, Australia.
Lovicu
F J
FJ
Ang
S L
SL
Pandey
S K
SK
McAvoy
J W
JW
D000199:Actins / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019923:Capsulorhexis; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007903:Lens Capsule, Crystalline / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology*; D018613:Microscopy, Confocal; D008875:Middle Aged; D008938:Mitosis / Q000187:drug effects; D051381:Rats; D046509:Tissue Culture Techniques; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism
D000199:Actins; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D018021:Lithium Chloride