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Aquaporin-3-Dependent Cell Migration and Proliferation during Corneal Re-epithelialization

From the Departments of Medicine and Physiology, Cardiovascular Research Institute, Graduate Group in Biophysics, University of California, San Francisco, California.

PURPOSE. To determine a role for the water- and glycerol-transporting protein aquaporin-3 (AQP3) in mammalian corneal epithelium, where it is expressed but has no known function.

METHODS. Corneal epithelial water and glycerol permeabilities were measured in living wild-type and AQP3-null mice using calcein fluorescence-quenching and ¹⁴C-glycerol-uptake assays, respectively. After removal of the corneal epithelium by scraping, re-epithelialization was followed by fluorescein staining. The contribution of AQP3-facilitated cell migration to corneal re-epithelialization was assessed using an organ culture model, in which initial resurfacing results from epithelial cell migration, as shown by BrdU analysis and 5-fluorouracil insensitivity, and by scratch wound assay using primary cultures of corneal epithelial cells from wild-type versus AQP3-null mice. Involvement of AQP3 in epithelial cell proliferation was investigated by morphometric and BrdU analysis of histologic sections, and by measurement of [³H]thymidine uptake in primary cultures of corneal epithelial cells.

RESULTS. AQP3 deficiency did not alter corneal epithelial thickness, morphology, or glycerol content, though both water and glycerol permeabilities were reduced. Time to corneal re-epithelialization in vivo was significantly delayed in AQP3-null mice compared to wild-type mice. Delays were also found in organ and primary cultures, demonstrating a distinct defect in cell migration arising from AQP3 deletion. Delayed restoration of full-thickness epithelia of AQP3-null mice over days after scraping suggested a separate defect in epithelial cell proliferation, which was confirmed by reduction in proliferating BrdU-positive cells in AQP3-deficient mice during healing, and by reduced proliferation in primary cultures of corneal epithelial cells from AQP3-null mice.

CONCLUSIONS. The significant impairment in corneal re-epithelialization in AQP3-deficient mice results from distinct defects in corneal epithelial cell migration and proliferation. The results provide evidence for involvement of an aquaporin in cell proliferation and suggest AQP3 induction as a possible therapy to accelerate the resurfacing of corneal defects.

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