Research On The Regulation Of HGF, ERK/MAPK, ESM And CNTF Signaling Pathways To Hepatocyte Differentiaiton During Rat Liver Regeneration

The liver has various physiological functions and a vigorous ability of regeneration. Induced byphysical, chemical, biological and other factors, the remnant liver cells proliferate rapidly from thequiescent G0phase into the cell cycle to compensate the loss of liver tissue and restore the biologicalfunction of the liver, this process is known as liver regeneration (LR). Studies have shown that LR involvesin cell activation, de-differentiation, cell proliferation and regulation, re-differentiation, reconstruction oftissue structure and function. Hepatocytes are one kind of the main parenchymal cells of the liver, whichaccount for65%of the total number of liver cells and70～80%of hepatic mass play an important role inliver regeneration.After partial hepatectomy or injury, a variety of cell signalings are activated to participate LR.Among them, cell differentiation is regulated by cell differentiation signalings. This study focuses onphysiological activity cell differentiation. Cell differentiation is the process that descendants of a kind ofcell occurs differences stability, and is regulated by cell differentiation signalings. In order to understandthe mechanism underlying the ways and means of cell differentiation signalings regulating hepatocytedifferentiation during rat liver regeneration, we respectively used Ingenuity Pathway Analysis9.0(IPA)software to determine signaling pathways and genes associated with cell differentiation,"Function andDisease" tool of IPA to find and confirm cell differentiation associated genes. Rat Genome2302.0Array todetermine the expression level of above genes,-Log(p-Value) and F-test to determine the celldifferentiation trends. The results showed that hepatocyte differentiation activities regulated byERK/MAPK and CNTF signaling pathways in PH group and those of SO group were very significantdifference(P≤0.01), hepatocyte differentiation activities regulated by HGF and ESM signaling pathways inPH group and those of SO group were significant difference(P≤0.05), indicating that the four signalingpathways are involved in cell differentiation during liver regeneration. The other signaling pathways suchas FGF pathway, protein kinase A pathway were not found to be significant between PH and SO groups.Then, we used Expression profile function（Ep）to calculate the gene expression change of signalingpathways, and the results showed that the Ep values of signal transduction activities of MKK/JNK branchin HGF signaling pathway, ERK/MAPK signaling pathway, JAK/STAT and Wnt branches in ESM signaling pathway, JAK/STAT and PI3K/AKT branches in CNTF signaling pathway were significantlyhigher than those of the control group during the whole process of LR. The Ep values of Ras/ERK branchin HGF signaling pathway were significantly higher in the progressing phase during LR. Finally, we usedExpression profile function（Ep）and network analysis techniques to analyse the ways and means of celldifferentiation signalings regulating hepatocyte differentiation during rat liver regeneration, and the resultsshowed that ERK/MAPK signaling pathway and Wnt branch in ESM signaling pathway promotedhepatocyte differentiation during the whole process of LR. JAK/STAT branch in ESM signaling pathway,JAK/STAT branch and PI3K/AKT branch in CNTF signaling pathway, and STAT branch in HGF signalingpathway promoted hepatocyte differentiation in the priming phase during LR. MKK/JNK branch in HGFsignaling pathway promoted hepatocyte differentiation in the progressing phase. Ras/ERK branch in HGFand ESM signaling pathways promoted hepatocyte differentiation in the terminal phase. Conclusions:41cell differentiation signaling pathways regulated cell differentiation, wherein HGF, ESM, ERK/MAPK andCNTF signaling pathways and their seven branches played a major role in promoting hepatocytedifferentiation in the regenerating liver.