No abstract

Liver regeneration, following partial hepatectomy (PHx), occurs through precisely controlled and synchronized cell proliferation, in which quiescent hepatocytes undergo one to two rounds of replication, with restoration of liver mass and function. We previously demonstrated that loss of the Smad3/4 adaptor protein b-2 spectrin (b2SP) is associated with faster entry into S phase, and hepatocellular cancer formation. These observations led us to further pursue the role of b2SP in cell cycle progression in vivo. Liver regeneration studies with PHx in b2SP 1/2 mice reveal a surprising and significant decrease in liver/ body weight ratio at 48 hours after PHx in b2SP 1/2 mice in comparison to wildtype mice. At 48 hours after PHx we also observe decreased levels of cyclin E (2.4-fold, P < 0.05), Cdk1 (7.2-fold, P < 0.05), cyclin A, pRb (Ser249/Thr252), proliferative cell nuclear antigen (PCNA), cyclin D1 with elevated levels of pCdk1 (Thr14) (3.6-fold, P < 0.05). Strikingly, at 24 hours elevated levels of p53 (4-fold, P < 0.05), phospho-p53 (ser15 and ser20), and p21 (200-fold, P < 0.05) persisting to 48 hours after PHx further correlated with raised expression of the DNA damage markers pChk2 (Thr68) and cH2AX (S139). However, compromised cell cycle progression with loss of b2SP is not rescued by inhibiting p53 function, and that G 2 /M phase arrest observed is independent and upstream of p53. Conclusion: b2SP deficiency results in dysfunctional hepatocyte cell cycle progression and delayed liver regeneration at 48 hours after PHx, which is p53-independent. b2SP loss may increase susceptibility to DNA damage, impair cell cycle progression, and ultimately lead to hepatocellular cancer. (HEPATOLOGY 2011;53:1641-1650 L iver regeneration represents an example of precisely controlled and synchronized cell proliferation in vivo. Following two-thirds partial hepatectomy (PHx), 95% of normally quiescent hepatocytes exit G 0 , rapidly reenter the cell cycle, and undergo one or two rounds of replication, with restoration of liver mass and function.1 Cell cycle progression proceeds in a synchronized pattern following PHx. In mid to late G 1 , phosphorylation of the retinoblastoma protein (Rb) by Cdk4/6-cyclin D complexes initiates the cell cycle and mediates the G 1 /S-phase transition.2 Cdk2 then successively associates withAbbreviations: b2SP, b-2 spectrin; CKIs, cyclin-dependent-kinase-inhibitory proteins; ELF, embryonic liver fodrin; MAPK, mitogen-activated protein kinase; MEFs, mouse embryonic fibroblasts; MT, b2SP mutant; PHx, partial hepatectomy; TGFb, transforming growth factor beta.From the

The combination of adipose tissue-derived stem cells and nonanimal stabilized hyaluronic acid holds promise as a tool with which to achieve lasting volume fill in reconstructive surgical soft-tissue augmentation.