THE COMBINATION OF EPIDERMAL GROWTH-FACTOR AND TRANSFORMING-GROWTH-FACTOR-BETA INDUCES NOVEL PHENOTYPIC CHANGES IN MOUSE-LIVER STEM-CELL LINES

Mouse liver stem cell (oval cell) lines were investigated in order to determine the role which two families of growth and differentiation fa ctors (GDFs), epidermal growth factor (EGF) family and transforming gr owth factor beta (TGF-beta) family, play in liver regeneration. EGF fa mily members, including EGF, amphiregulin, betacellulin, heparin-bindi ng epidermal growth factor, and TGF-alpha, were mitogenic for oval cel l lines while TGF-beta family members, including TGF-beta 1, TGF-beta 2 and TGF-beta 3, inhibited mitogenesis and induced apoptosis in oval cell lines, Surprisingly, the combination of EGF family members and TG F-beta family members resulted in neither proliferation nor apoptosis but instead in a novel cellular response, cellular scattering in tissu e culture and morphological differentiation in Matrigel, Analysis of t he signal transduction pathways activated by exposure of oval cell lin es to either EGF, EGF + TGF-beta, or TGF-beta indicated that novel com binations of intracellular signals result following stimulation of the cells with the combination of EGF + TGF beta. These data reveal that the dynamics of synergistic GDF action following tissue injury and reg eneration results in a new level of complexity not obvious from the st udy of individual GDFs.