Gene Expression Profile at the G1/S Transition of Liver Regeneration after Partial Hepatectomy in Mice

Abstract

Liver is a quiescent organ with >90% of the cells present in the G 0 stage of the cell cycle. However, adult hepatocytes have enormous ability to proliferate in response to liver injury. After 70% liver resection hepatocytes enter the cell cycle in a highly synchronized manner and undergo 1 to 2 rounds of cell division to restore the lost organ mass, thus, representing one of the most reliable model systems to study cell cycle progression in vivo. Using high density oligonucleotide micro-array we analyzed the expression patterns of genes at the G 1 /S transition of liver regeneration in comparison to quiescent livers. The G 1 /S boundary was identified by in vivo BrdU pulse labeling and we observed 199 genes/ESTs which were either up/down regulated at this time point. These differentially regulated genes have a wide range of functions including transcriptional regulation, signal transduction, cell cycle regulation, chromatin reorganization, protein targeting, metabolism, transport, surface receptors, circadian rhythms, xenobiotic metabolism, inflammation and acute phase response. The functions of most of the genes identified in this screen are not known in the process of liver regeneration and cell cycle control at G 1 /S transition.

T160‐phosphorylated CDK2 defines threshold for HGF‐dependent proliferation in primary hepatocytes

“…We have previously shown that in our ex vivo culture system, primary mouse hepatocytes complete DNA replication after 48 h of HGF stimulation (Huard et al , 2012 ). This result is congruent with in vivo data of partially hepatectomized mice where the peak of DNA synthesis occurs between 36 and 48 h post-surgery (Satyanarayana et al , 2004 ; Michalopoulos, 2007 ). Furthermore, we determined that the restriction point occurs after approximately 32 h of HGF stimulation in primary mouse hepatocytes.…”

“…Furthermore, we determined that the restriction point occurs after approximately 32 h of HGF stimulation in primary mouse hepatocytes. This is in line with gene expression studies addressing the G1/S transition after two-thirds PHx in C57BL/6 mice that identified a time frame of 30–36 h for this crossing point (Satyanarayana et al , 2004 ). These data indicate a good correlation for the timing of the G1/S transition and the restriction point between mouse hepatocytes ex vivo and in vivo .…”

Post-hepatectomy liver regeneration in the context of bile acid homeostasis and the gut-liver signaling axis

“…Liver regeneration entails the activation of multiple regulatory pathways that include cytokine-, growth factor-, and metabolic networks [40]. More specifically, PHx induces differential regulation of genes that coordinate cell cycle regulation, chromatin reorganization, transcriptional regulation, signal transduction, protein targeting, metabolism, transport, xenobiotic metabolism, surface receptors, inflammation, and acute phase responses [41]. These pathways are well- coordinated to allow proper restoration of the tissue while maintaining vital liver functions.…”

SHP2 inhibition enhances Yes-associated protein–mediated liver regeneration in murine partial hepatectomy models

“…For example, Saa3 transcript expression was increased following NSC administration. Saa3 is an acute phase reactant specific to mice, a pseudogene in humans, that has been shown to be associated with liver regeneration following partial hepatectomy and may be important for metabolic adaptation and cellular protection ( 56 , 57 ). Notable genes that were downregulated by NSC treatment included Egr2 and Ddit3 .…”