DIFFERENTIAL TUBULOGENIC AND BRANCHING MORPHOGENETIC ACTIVITIES OF GROWTH-FACTORS - IMPLICATIONS FOR EPITHELIAL TISSUE-DEVELOPMENT

At least two kidney epithelial cell lines, the Madin-Darby canine kidn ey (MDCR) and the murine inner medullary collecting duct line mIMCD-3, can be induced to form branching tubular structures when cultured wit h hepatocyte growth factor (HGF) plus serum in collagen I gels, In our studies, whereas MDCK cells remained unable to form tubules in the pr esence of serum alone, mIMCD-3 cells formed impressive branching tubul ar structures with apparent lumens, suggesting the existence of specif ic factors in serum that are tubulogenic for mIMCD-3 cells but not for MDCK cells. Since normal serum does not contain enough HGF to induce tubulogenesis, these factors appeared to be substances other than HGF. This was also suggested by another observation: when MDCK cells or mI MCD-3 cells were cocultured under serum-free conditions with the embry onic kidney, both cell types formed branching tubular structures simil ar to those induced by HGF; however, only in the case of MDCK cells co uld this be inhibited by neutralizing antibodies against HGF. Thus, th e embryonic kidney produces growth factors other than HGF capable of i nducing tubule formation in the mIMCD-3 cells. Of a number of growth f actors examined, transforming growth factor alpha (TGF-alpha) and epid ermal growth factor (EGF) were found to be tubulogenic for mIMCD-3 cel ls. Whereas only HGF was a potent tubulogenic factor for MDCK cells, H GF, TGF-alpha, and EGF were potent tubulogenic factors for mIMCD-3 cel ls. Nevertheless, there were marked differences in the capacity of the se tubulogenic factors to induce tubulation as web as branching events in those tubules that did form (HGF >> TGF-alpha > EGF). Thus, at lea st three different growth factors can induce tubulogenesis and branchi ng in a specific epithelial cell in vitro (though to different degrees ), and different epithelial cells that are capable of forming branchin g tubular structures demonstrate vastly different responses to tubulog enic growth factors, The results are discussed in the context of branc hing morphogenesis during epithelial tissue development.