The growth-promoting effect of KGF on limbal epithelial cells is mediated by upregulation of DeltaNp63alpha through the p38 pathway.
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 DeltaNp63alpha expression by KGF is mediated via the p38 pathway. The effect of KGF on limbal epithelial outgrowth was significantly reduced when endogenous DeltaNp63alpha was suppressed, suggesting that KGF-induced limbal epithelial outgrowth is dependent on the expression of DeltaNp63alpha. Our findings strongly suggest that limbal keratocytes regulate limbal epithelial cell growth and differentiation through a KGF paracrine loop, with DeltaNp63alpha expression as one of the downstream targets.
Cheng
Chien-Chia
CC
Department of Physiology, College of Medicine, Chang Gung University, Kweishan, Taoyuan 333, Taiwan.
Wang
Der-Yuan
DY
Kao
Ming-Hui
MH
Chen
Jan-Kan
JK
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019573:Epithelium, Corneal / Q000166:cytology* / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D053547:Keratin-14 / Q000378:metabolism; D053558:Keratin-3 / Q000378:metabolism; D016850:Limbus Corneae / Q000166:cytology* / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D053547:Keratin-14; D053558:Keratin-3; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051523:Fibroblast Growth Factor 7; D017228:Hepatocyte Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases