Involvement of ERK1/2 signaling in proliferation of eight liver cell types during hepatic regeneration in rats

Abstract

ABSTRACT. It has been well established that ERK1/2 signaling, often subdivided into nine types of pathways, can regulate the hepatocyte proliferative response during liver regeneration. However, the effect of ERK1/2 signaling on the proliferation of other hepatic cell types remains unclear. We isolated and purified 8 liver cell types at 10 time points after 2/3 hepatectomy in adult rats. For each cell type, mRNA expression changes for ERK1/2 signaling-involved genes were monitored up to 168 h, using microarrays. Real-time PCR assays were performed for array data verification. The expression levels of these genes varied considerably between different cell types. Integrating microarray results with gene synergical analysis, at the priming phase, activation of integrin/Grb2/Ras pathway in hepatocytes apparently contributed to G0/G1 transition. Two other pathways, G-protein/EPAC/Rap1 and G-protein/PKA/Rap1, were stimulated in hepatic stellate cells, while RTK/PKC/Ras and RTK/Grb2/Ras were stimulated in Kupffer cells. At the progressive phase, the ERK1/2 pathway is involved in hepatocyte replication; three pathways, namely Ca G-protein/EPAC/Rap1, were found to play roles in biliary epithelial cell proliferation, while RTK/PKC/Ras and RTK/Grb2/Ras were involved in Kupffer cell proliferation, and G-protein/PKC/Ras in pit cell proliferation. At the terminal phase, the promotive effect of the ERK1/2 pathway on replication of hepatocytes, biliary epithelial cells, oval cells, hepatic stellate cells, Kupffer cells, and dendritic cells was considerably reduced, possibly due to their differentiation at the end of regeneration. G-protein/PKC/Ras, integrin/Grb2/Ras and G-protein/ PKA/Rap1 pathways were active in sinusoidal endothelial cells, perhaps to aid in their proliferation. We conclude that ERK1/2 has a signaling role in the regulation of proliferation of 8 cell types during liver regeneration process.

Kruppel-like factor 2 inhibit the angiogenesis of cultured human liver sinusoidal endothelial cells through the ERK1/2 signaling pathway

“…It has also been reported that ERK1/2 signaling pathway can positively regulate proliferation of LSECs [33] and the phosphorylation of ERK1/2 increases HIF-1a expression, thus promoting the production of classical angiogenic factors such as VEGF [34]. Our present study indicated that overexpression of KLF2 inhibited the activation of p-ERK1/2, and after blocking ERK1/2 with the specific inhibitor PD98059, the inhibitory effect of KLF2 on LSEC proliferation and migration was also blocked.…”

“…The ERK1/2 signaling pathway is known to play an important role in endothelial proliferation and migration, which are two essential procedures in the process of angiogenesis [33]. It has also been reported that ERK1/2 signaling pathway can positively regulate proliferation of LSECs [33] and the phosphorylation of ERK1/2 increases HIF-1a expression, thus promoting the production of classical angiogenic factors such as VEGF [34].…”

Biochemical and Molecular Mechanisms of Platelet-Rich Plasma in Ameliorating Liver Fibrosis Induced by Dimethylnitrosurea

“…Hepatocytes are the primary cells to enter the cell cycle and undergo proliferation. Hepatocytes produce mitogenic signals for other types of liver cells, and every mediator drives the downstream cascades, which transfer hepatocytes from the quiescent state to the cell cycle [29].TNF-α/NF-κB, IL-6/signal transducer and activator of interpretation 3 (STAT3), phosphatidylinositol-3-kinase (PI3K)/Akt, HGF/HFG receptor (cMet), and extracellular signal-regulated kinase 1/2 (ERK1/2) are all important pathways involved in liver recovery [30]. The aforementioned mechanisms clarify the role of PRP in improving liver fibrosis because of its high content of growth factors.…”

RNA-Seq transcriptome profiling in three liver regeneration models in rats: comparative analysis of partial hepatectomy, ALLPS, and PVL

“…This has made the liver an excellent model for studying organ regeneration [1][2][3][4] . The regenerative process is typically divided into the priming, proliferating and termination phases, occurring approximately at first, third and seventh days after resection, respectively 5 . Clinically, the regenerative ability of livers provides the cornerstone of many surgical treatments for liver diseases; resection of diseased portions seems to improve survival 6 .…”