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First published online 17 November 2009
doi: 10.1242/jcs.054791

Journal of Cell Science 122, 4473-4480 (2009)
Published by The Company of Biologists 2009
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Research Article

The growth-promoting effect of KGF on limbal epithelial cells is mediated by upregulation of {Delta}Np63{alpha} through the p38 pathway

Chien-Chia Cheng1, Der-Yuan Wang2, Ming-Hui Kao2 and Jan-Kan Chen1,*

1 Department of Physiology, College of Medicine, Chang Gung University, Kweishan, Taoyuan 333, Taiwan
2 Section of Blood Products & IVDs, Drug Biology Division, Bureau of Food and Drug Analysis, Department of Health, Taiwan

* Author for correspondence (jkc508{at}mail.cgu.edu.tw)

Accepted 26 September 2009

Corneal epithelial stem cells are thought to reside in the limbus, the transition zoon between cornea and conjunctiva. Keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) are two paracrine factors that regulate the proliferation, migration and differentiation of the limbal epithelial cells; however, the underlying mechanisms are still poorly understood. In an ex vivo limbal explant culture, we found that KGF is a more potent growth stimulator for the epithelial outgrowth than HGF. Immunofluorescence studies of the epithelial outgrowth from cells treated with HGF or KGF showed similar expression patterns of keratin-3 and keratin-14. Interestingly, p63 was highly expressed in KGF-treated limbal epithelial sheets but not in those treated with HGF. Kinase inhibitor studies showed that induction of {Delta}Np63{alpha} expression by KGF is mediated via the p38 pathway. The effect of KGF on limbal epithelial outgrowth was significantly reduced when endogenous {Delta}Np63{alpha} was suppressed, suggesting that KGF-induced limbal epithelial outgrowth is dependent on the expression of {Delta}Np63{alpha}. Our findings strongly suggest that limbal keratocytes regulate limbal epithelial cell growth and differentiation through a KGF paracrine loop, with {Delta}Np63{alpha} expression as one of the downstream targets.

Key words: Limbus, Cornea, Stem cell, Epithelium, KGF, {Delta}Np63{alpha}


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