Aquaporin-3 facilitates epidermal cell migration and proliferation during wound healing
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Healing of skin wounds is a multi-step process involving the migration and proliferation of basal keratinocytes in epidermis, which strongly express the water/glycerol-transporting protein aquaporin-3 (AQP3). In this study, we show impaired skin wound healing in AQP3-deficient mice, which results from distinct defects in epidermal cell migration and proliferation. In vivo wound healing was ~80% complete in wild-type mice at 5 days vs ~50% complete in AQP3 null mice, with remarkably fewer proliferating, BrdU-positive keratinocytes. After AQP3 knock-down in keratinocyte cell cultures, which reduced cell membrane water and glycerol permeabilities, cell migration was slowed by more than twofold, with reduced lamellipodia formation at the leading edge of migrating cells. Proliferation of AQP3 knock-down keratinocytes was significantly impaired during wound repair. Mitogen-induced cell proliferation was also impaired in AQP3 deficient keratinocytes, with greatly reduced p38 MAPK activity. In mice, oral glycerol supplementation largely corrected defective wound healing and epidermal cell proliferation. Our results provide evidence for involvement of AQP3-facilitated water transport in epidermal cell migration and for AQP3-facilitated glycerol transport in epidermal cell proliferation.
KeywordsAQP3 Wound healing Cell migration Cell proliferation Glycerol transport
mitogen-activated protein kinase
We thank Liman Qian for mouse breeding and genotype analysis. This work was supported by NIH grants DK35124, EY13574, EB00415, HL59198, HL73856, and DK72517 and Research Development Program and Drug Discovery grants from the Cystic Fibrosis Foundation.
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