Analyses of Jagged1 and Notch1 in Rat‐ and Human‐ Hepatocyte Culture: Differentiation and Proliferation Conditions affect receptor and ligand of Notch Pathway.

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The Notch‐signaling pathway controls cell fate determination and differentiation, and its dysfunction is associated with Alagille syndrome or hepatocellular carcinoma. Our previous studies have shown that Notch and Jagged‐ siRNA treated rat liver reduces the ability in proliferation and regeneration following partial hepatectomy. To determine the putative role of Notch and Jagged in proliferation of hepatocytes, we analyzed expression of Jagged1 and Notch1 in the primary cultures of rat‐ and human hepatocytes. The hepatocytes were cultured in the presence or absence of HGF, EGF, TGFalpha, VEGF, Dexamethasone or Matrigel. Real‐time PCR and Western Blot analyses were performed to detect levels of Notch‐1, Jagged‐1 and target gene Hes‐1. Our results show that proliferative conditions for hepatocytes increase expression of Notch, Jagged or Hes. Whereas glucocorticoid induce expression of Notch and proliferation of endothelial cells, hepatocytes differentiate due to glucocorticoid induced downregulation of Notch. Hepatocytes surrounded by extracellular matrix downregulate Notch‐signaling and promote differentiation in vitro. The above results indicate that Notch signaling depend on factors, which are involved in differentiation or proliferation of hepatocytes. This supports our hypothesis that an equilibrium of cytokines and Notch‐signaling are necessary in controlled liver regeneration.