Mechanism of Liver Organogenesis and Its Application to Liver

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To clarify the mechanism of sinusoidal endothelial cell(SEC) proliferation after hepatectomy, the expression of vascular endothelial growth factor(VEGF) and VEGF-receptor of the regenerating liver were evaluated with 70% hepatectomy model in the rats. The expression of VEGF mRNA was increased markedly between 48 and 72 hr after hepatectomy. The immunohistochemical staining revealed that expression of VEGF started to increase 24 hr after hepatectomy, with a peak at 72 hr. Expression of flt-1 and KDR/flk-1 was observed along the sinusoids even before hepatectomy, but was increased between 72 and 120 hr. Furtheremore, VEGF production by cultured hepatocytes isolated 72 hr after hepatectomy was siginificantly increased. The PCNA labeling index of the SECs exhibited a delayed and slower regenerative response in comparison to the hepatocytes, teaching a peak at 72 hr. These data strongly suggest that VEGF secreted by proliferating hepatocytes may represent an important stimulator of SEC proliferation.Furthermore, we focused on the research of Angiopoietin-Tie system that has been shown to regulate liver organogenesis through the modulation of VEGF. Early endothelial cells in mouse embryo surround newly specified hepatic endoderm and delimit the mesenchymal domain into which the liver bud grows. In flk-1 mutant embryo, which lack endothelial cells, hepatic specification occurs, but liver morphogenesis fails prior to mesenchyme invasion. It is concluded that vasculogenic endothelial cells and nascent vessels are critical for the earliest stages of organogenesis, prior to blood vessel function.