Because NF-κB is assigned to only cluster V, in all other clusters predominant signaling pathways generated by IPA for the genes present were able to impute the NF-κB complex as a central node. These analyses indicate activation of signals promoting proliferation and AUY-922 concentration regeneration, apoptosis, and cell death. These gene expression changes are most likely mediated by inflammation and oxidative stress, and are associated with progressive loss of

gene expression representing worsening of metabolic function. Fig. 3b summarizes our inferences from these data, in which we suggest that clusters I, II, IV, and V are regulated by genes in cluster III (see Discussion). In addition, there was a progressive loss of telomerase activity, an increase in polyploidy, and a critical

shortening of telomere length (Fig. 4), indicating replicative senescence as cirrhosis led to decompensated liver function. HNF4-α was also found to be a central node in networks of expressed genes in each of the five cluster patterns identified (Supporting Fig. 3). The expression of HNF4-α expression progressively fell with worsening liver function, regulating function as seen in two of the highly ranked networks generated by the genes in EPZ-6438 ic50 cluster IV, indicating dedifferentiation of hepatocytes. Because HNF-4α is present only in cluster IV, it was imputed as a node in the networks generated by IPA for the genes present in all other clusters. Thus, hepatocytes derived from livers with progressive worsening cirrhosis appeared to be undergoing replicative senescence and dedifferentiation. This finding is further supported by studies showing that inhibitor of κB phosphorylation changes significantly, as expected, with severity of cirrhosis (Supporting Fig. 4a). To further characterize the cells isolated from these livers, we examined whether worsening cirrhosis generated liver progenitor cells. As cirrhosis progressed there was an associated check details increase in the percentage of cells

expressing alpha fetoprotein (data not shown), and putative liver progenitor cell markers CD44 and Epcam in liver sections (Fig. 5a-c). A nearly identical percentage of the cells isolated from cirrhotic livers expressed each of the marker proteins found in liver sections (Fig. 5d-f), indicating that the distribution of cell phenotypes derived from cirrhotic livers after isolation most likely represented that found in intact livers even though the cell yield following collagenase digestion from these livers was significantly lower than that obtained following digestion of control livers. To examine the extent to which the impaired function and the altered gene expression associated with isolated cells derived from cirrhotic livers is affected by their microenvironment, cells from the livers of cirrhotic and age-matched controls were transplanted into the livers of Nagase analbuminemic rats.