970 NEURONAL MICRORNAS, UPREGULATED DURING MYOFIBROBLASTIC DIFFERENTIATION, TARGET THE PLURIPOTENCY FACTOR LIN-28

POSTERSshowed that CcnE1 is a key player for hepatocyte proliferation during liver regeneration, while CcnE2 is a negative regulator of CcnE1.Liver fibrogenesis is associated with proliferation of hepatocytes and hepatic stellate cells (HSC).Thus, the aim of this study was to investigate the potential contribution of CcnE1 and CcnE2 for liver fibrosis in human and mice.Immunohistochemistry of human fibrotic liver sections displayed a significant increase of CcnE1 expression in hepatocytes and nonparenchymal cells hinting at an important role of CcnE1 in liver fibrosis.Accordingly, induction of liver fibrosis in wildtype (WT) mice by periodical administration of carbon tetrachloride (CCl 4 ) was also associated with induction of CcnE1 mRNA-and protein expression.Interestingly, liver fibrosis after CCl 4 treatment for 4 weeks was strongly diminished in CcnE1-/-mice compared to WT controls.Expression of collagen1-and a-SMA mRNA in these mice was lower compared to the WT group and in situ staining of collagen1 and a-SMA revealed less fiber formation and reduced numbers of a-SMA positive cells in CcnE1-/-animals.Interestingly, CcnE2 -/-mice presented earlier start of fiber formation at already 2 weeks of CCl 4 treatment.Time course experiments in primary HSC derived from WT mice demonstrated that the CcnE expression peak is associated with onset of HSC proliferation and precedes transdifferentiation into myofibroblasts.In contrast, CcnE1-/-HSC performed only incomplete cell cycles leading to S-phase arrest and strongly increased cell death.However, CcnE2 -/-HSC showed even earlier S-phase onset, earlier and prolonged a-sma expression, which was also correlated with high levels of CcnE1.Taken together our results point to an essential role of CcnE1 for fibrogenesis in man and mice and identify HSC as one target cell population for the pro-fibrogenic effect of CcnE1.As cyclin E2 depletion leads to earlier and stronger onset of S-phase progression of HSC, higher proliferation and higher a-SMA expression, we conclude that CcnE2 basically acts as a negative regulator of CcnE1.