Human liver samples were available from routine liver biopsies or from explanted cirrhotic livers this website resulting from transplantation, as described recently.13 The study protocol was approved by the local ethics committee (ethics committee of University Hospital Aachen, RWTH Aachen, Aachen, Germany), and the study was conducted according to the principles expressed

in the Declaration of Helsinki. Animal husbandry and procedures were approved by the authority for environment conservation and consumer protection of the state of North Rhine–Westfalia (LANUV, Germany) and the University Hospital Aachen Animal Care Facility’s guidelines. For our study, we used mice of Carfilzomib concentration male gender with constitutive deletion of CcnE1 (CcnE1−/−) and CcnE2 (CcnE2−/−)

and wild-type (WT) littermates from heterozygous breeding couples, as recently reported.9, 11 HSCs were prepared from adult male mice (weighing approximately 25 g), according to the collagenase method,14 as described in the Supporting Materials. Data are expressed as mean ± standard deviation of the mean. Statistical significance was determined by two-way analysis of variance, followed by a Student t test. E-type cyclins CcnE1 and CcnE2 control the transition of quiescent cells into the S phase and subsequent cell 上海皓元 proliferation.4 We hypothesized that liver fibrogenesis involves the cell proliferation of hepatic cell populations and determines overall CcnE expression in liver biopsies from patients

with liver fibrosis of different etiologies (see Supporting Table 1). CcnE1 mRNA expression was significantly up-regulated in patients with advanced hepatic fibrosis (F3) and liver cirrhosis (F4), compared to healthy control livers (F0) or patients with mild (F1) fibrosis (Fig. 1A). In contrast, CcnE2 was not aberrantly expressed in liver fibrosis at any stage (Fig. 1B). Immunostaining of liver biopsies confirmed the overexpression of CcnE1 in liver cirrhosis (Fig. 1C). Detailed analysis revealed the substantial nuclear expression of CcnE1 in nonparenchymal cells (NPCs), but also in hepatocytes of cirrhotic livers, which was not observed in healthy liver samples (Fig. 1D). We next investigated the involvement of CcnE1 in experimental liver fibrosis in WT mice subjected to repetitive CCl4 injections. In agreement with the human samples, mRNA expression of CcnE1, but not of CcnE2, was induced in murine liver after CCl4 treatment and correlated with fibrosis progression (Fig. 2A).