Fig. 1

Schematic overview of liver regeneration after 2/3 PH. After partial hepatectomy, the remaining liver cells proliferate until the original organ size is restored. Three phases of liver regeneration have been identified: (1) priming, (2) proliferation, and (3) termination. The priming phase (1) is related to the activation of growth factors (HGF and EGF, which are ligands of MET and EGF receptors, respectively), induced by the 2/3 PH-induced increase in μPA and the nuclear translocation of Notch1 and beta-catenin into hepatocytes, as well as by the release of cytokines (TNF-α; norepinephrine, bile acids, IL-6, serotonin) that modulate hepatocyte proliferation and the interaction between hepatocytes and non-parenchymal cells. The proliferation phase (2) is preceded by activation and nuclear translocation of transcription factors such as STAT3, C/EBPβ, and NFκB. Increased expression of IEGs (c-Fos, c-Jun, and c-Myc) is also observed. All these factors promote the proliferation phase, leading to the transcription of cyclin genes. Proliferating hepatocytes release many growth factors that stimulate the proliferation of non-parenchymal cells: VEGF and Ang1 and 2, mitogenic for LSECs; TGF-α, mitogenic for endothelial cells, LSECs, and HSCs; FGF1 and 2, mitogenic for HSCs and LSECs; and GM-CSF, which stimulates the proliferation of KCs. In addition, microRNAs (miRNAs) were also found to be involved in the regulation of hepatocyte DNA synthesis in mouse models of liver regeneration. The termination phase (3) is likely promoted by activation of signal transduction pathways that suppress cell growth, such as that mediated by TGF-β/TGFβ receptor and HNF-4α