Hepatocyte growth factor expression in the developing myocardium: Evidencefor a role in the regulation of the mesenchymal cell phenotype and urokinase expression

During development of the heart, the endocardium of the developing cushion tissue transforms into mesenchymal cells that rapidly invade the underlying extracellular matrix. This invasive process, along with subsequent prolife ration and differentiation of the mesenchyme, are essential for the normal formation of valvular and septal structures. Several factors have been iden tified that appear to initiate and/or control this transformation process, including the growth factor TGF-beta. In these studies we have investigated whether hepatocyte growth factor/scatter factor (HGF/SF) may also be invol ved in some aspects of this transformation process. Using an immunohistoche mical approach we have detected a spatially restricted localization of HGF/ SF to the myocardial cells of the cushion tissue. HGF was detected in extra cts of the developing heart, and the presence of the active form correlated with the onset of the transformation process and the elevation of urokinas e activity. The endocardial-derived mesenchymal cells of the cushion tissue were found to express the c-met HGF receptor. Isolated endocardial cells r esponded to the addition of HGF with increases in motility, proliferation, and urokinase production. The results from these studies suggest that HGF m ay function as a myocardial-derived mediator of the epithelial-mesenchymal transformation by inducing and/or maintaining the mesenchymal cell phenotyp e, The increase in urokinase expression by the cushion tissue cells, in res ponse to HGF, may facilitate the invasive abilities of these cells and also provide a means of maintaining high levels of active HGF required for the stimulation of cell proliferation and migration. Dev Dyn 1999;214:92-100. ( C) 1999 Wiley-Liss, Inc.