HEPATOCYTE GROWTH-FACTOR (HGF) ACTS AS A MESENCHYME-DERIVED MORPHOGENIC FACTOR DURING FETAL LUNG DEVELOPMENT

Mesenchymal-epithelial tissue interactions are important for developme nt of various organs, and in many cases, soluble signaling molecules m ay be involved in this interaction. Hepatocyte growth factor (HGF) is a mesenchyme-derived factor which has mitogenic, motogenic and morphog enic activities on various types of epithelial cells and is considered to be a possible mediator of epithelial-mesenchymal interaction durin g organogenesis and organ regeneration. In this study, we examined the role of HGF during lung development. In situ hybridization analysis s howed HGF and the c-met/HGF receptor gene to be respectively expressed in mesenchyme and epithelium in the developing lung, In organ culture s, exogenously added HGF apparently stimulated branching morphogenesis of the fetal lung. In contrast, HGF translation arrest or neutralizat ion assays resulted in clear inhibition of epithelial branching, These results suggest that HGF is a putative candidate for a mesenchyme-der ived morphogen regulating lung organogenesis. We also found that HGF i s involved in epithelial branching, in collaboration with fibroblast g rowth factor (FGF) family molecule(s), In mesenchyme-free culture, HGF alone did not induce epithelial morphogenesis, however, addition of b oth HGF and acidic FGF (aFGF) or keratinocyte growth factor (KGF), lig ands for the KGF receptor, induced epithelial branching more extensive ly than that was observed in explants treated with aFGF or KGF alone. In addition, the simultaneous inhibition of HGF-and FGF-mediated signa ling using neutralizing antibody and antisense oligo-DNA resulted in d rastic impairment of epithelial growth and branching, Possible interac tions between HGF and FGFs or other growth factors in lung development is given consideration.