POSTERS indicates that cell-cell interactions, rather than soluble factors from liver-myofibroblasts, play a role in enhancing the trans- differentiation of liver progenitor cells into hepatocytes. Conclusions: These data identify an important role for liver myofibroblasts in progenitor cell trans-differentiation into hepatocytes through cell-cell interactions. Supported by an MRC ITTP Studentship. Reference(s) [1] Resnick, J.L., Ortiz, M., Keller, J.R., Donovan, P.J. 1998, Biol Rep 59, 1224– 1229. [2] Wallace, K., Marek, C.J., Hoppler, S., Wright, M.C. 2010, J Cell Sci 15, 2103–2110. 1083 HEPATIC NK AND NKT CELLS COOPERATIVELY REGULATE LIVER REGENERATION AFTER PARTIAL HEPATECTOMY IN MICE S. Hosoya 1 , K. Ikejima 1 , K. Arai 1 , T. Aoyama 1 , K. Kon 1 , S. Ishikawa 1 , H. Yamagata 1 , S. Yamashina 1 , K. Takeda 2 , S. Watanabe 1 . 1 Department of Gastroenterology, 2 Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan E-mail: shosoya@juntendo.ac.jp Background and Aims: Liver regeneration is impaired in obese, diabetic rodents developing spontaneous steatohepatitis such as ob/ob and KK-A y mice, in which hepatic NKT cells are depleted. In this study, we investigated the differences in hepatic regeneration after partial hepatectomy (PH) in mice selectively depleted NK and/or NKT cells. Methods: Male, 12 week-old CD1d-knockout (KO) mice, which lack NKT cells systemically, and wild type (WT; C57Bl/6) mice were used. Some mice were pretreated with NK1.1 or asialo-GM1 antibody 24 hr prior to experiments to deplete NK/NKT cells or NK cells alone, respectively. Mice underwent the 2/3 PH, and the uptake of BrdU and the expression of PCNA in hepatocyte nuclei were detected by immunohistochemistry. Hepatic expression levels of cyclin D1 and IFNg mRNA were analyzed quantitatively by Western blotting and real time RT-PCR, respectively. Results: In CD1d-KO mice, BrdU uptake and PCNA expression were almost similar to those in WT mice 48 hr after PH, the labeling indices being nearly 20% and 30%, respectively. In sharp contrast, both parameters after PH was decreased remarkably in WT mice pretreated with an NK1.1 antibody, values reaching only 1.7% and 11.9%, respectively (P < 0.01 vs. WT after PH). Further, expression of cylin D1 in the liver 48hr after PH was nearly normal in CD1d-KO mice, but the levels were almost completely blunted in mice given an NK1.1 antibody. Interestingly, CD1d-KO mice given an asialo- GM1 antibody showed impaired regenerative responses as similar to WT mice given an NK1.1 antibody. Hepatic IFNg mRNA was elevated nearly 5-fold in WT mice 6 hr after PH, which was not affected by pretreatment with an NK1.1 antibody. Conclusions: These findings clearly indicated that liver regeneration is markedly impaired when both NKT and NK cells are depleted in two different preparations. NK cell-function under regeneration appears to be paradoxical in the presence or absence of NKT cells, and it is unlikely that IFNg plays a regulatory role in regeneration failure caused by simultaneous depletion of NK and NKT cells. It is therefore concluded that NKT and NK cells are coordinately involved in normal regenerative responses in the liver. 1084 CYCLIN E1 AND D1 CAN DRIVE LIVER REGENERATION IN MICE WITHOUT CDK2 W. Hu 1 , Y.A. Nevzorova 1 , J.R. Nowak 1 , U. Haas 1 , N. Moro 1 , Y. Geng 2 , P. Sicinski 2 , M. Barbacid 3 , C. Trautwein 1 , C. Liedtke 1 . 1 Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Aachen, Germany; 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; 3 Centro Nacional de Investigaciones Oncol´ ogicas (CNIO), Madrid, Spain E-mail: whu@ukaachen.de Background and Aims: The liver has a strong capacity to regenerate in response to injury. For this process, remnant hepatocytes leave their quiescent state, re-enter the cell cycle and start to proliferate until liver mass and function are restored. In vitro studies have indicated that cyclin-dependent kinase 2 (Cdk2) is an important cell cycle mediator driving initiation and progression of DNA-synthesis via complex formation with E- and A-type cyclins, respectively. The aim of the current study was to evaluate the role of Cdk2 for liver regeneration. Methods: Hepatocyte-specific Cdk2 knockout mice (Cdk2 Dhepa ) and wild type (WT) controls were subjected to partial hepatectomy (PH) and analyzed for liver regeneration. Alternatively, Cdk2 and Cdk1 were simultaneously blocked in vitro and in vivo using the Cdk-inhibitor roscovitine. Results: Following PH, liver regeneration was unaffected by the loss of Cdk2 and resulted in normal hepatocyte proliferation in Cdk2 Dhepa mice comparable to WT controls. We thus analyzed the mechanisms responsible for compensation of Cdk2-deficiency. Liver regeneration in Cdk2 Dhepa mice was associated with elevated levels of cyclin D1 (CcnD1) and cyclin E1 (CcnE1). Stronger CcnD1 expression resulted in accelerated and enhanced CcnD1-dependent kinase activity whereas over-expression of CcnE1 in Cdk2 Dhepa mice was not associated with kinase activation. A proposed and in part kinase- independent function of CcnE1 is the involvement in pre-replication complex (pre-RC) formation via interaction with minichromosome maintenance (MCM) proteins. We provide evidence that mitogenic activated, primary Cdk2 -/ - hepatocytes displayed an earlier onset of pre-RC formation associated with premature expression of the CcnE1, Cdt1 and MCM2 and their physical interaction with chromatin. Combined inhibition of Cdk2 and Cdk1 using roscovitine efficiently blocked hepatocyte proliferation in WT and Cdk2 Dhepa mice demonstrating that hepatocyte proliferation depends on Cdk1, but not on Cdk2. However, over-expression of CcnE1 in vitro or in vivo partially rescued Roscovitine-mediated cell cycle arrest further confirming kinase-independent functions of CcnE1 in the liver. Conclusions: Over-expression of CcnD1 and CcnE1 compensate Cdk2-deficiency via two mechanisms involving increased CcnD1- related kinase activity and a premature, cyclin E-dependent initiation of the pre-replication complex. 1085 REGENERATION IS SUPPRESSED IN ISCHEMICALLY INJURED LIVER AFTER 70% HEPATECTOMY THROUGH DECREASED ACTIVATION OF NF-KAPPAB S. Kuboki 1 , A.B. Lentsch 2 , F. Kimura 1 , H. Shimizu 1 , H. Yoshidome 1 , M. Ohtsuka 1 , A. Kato 1 , H. Yoshitomi 1 , K. Furukawa 1 , D. Takeuchi 1 , T. Takayashiki 1 , K. Suda 1 , M. Miyazaki 1 . 1 Department of General Surgery, Chiba University, Chiba, Japan; 2 Department of Surgery, University of Cincinnati School of Medicine, Cincinnati, OH, USA E-mail: satoshi.kuboki@faculty.chiba-u.jp Background and Aims: Ischemia preconditioning during hepate- ctomy is known to decrease hepatocyte damage and induce liver regereration. However, liver regeneration is suppressed in severe damaged liver after hepatectomy. We previously reported that CXC chemokines delayed liver regeneration after ischemia/reperfusion (I/R) injury through CXCR2, even though CXC chemokines have Journal of Hepatology 2011 vol. 54 | S363–S534 S429