Hematopoietic stem cells have potential in the field of regenerative medicine because of their capacity to form cells of different lineages. Bone marrow stem cells have been shown to contribute to parenchymal liver cell populations, and although this may not be functionally significant, it has sparked interest in the field of autologous stem cell infusion as a possible treatment for cirrhosis. In this review, we will examine the evidence for the contribution of bone marrow-derived cells to populations of liver cells and for the functional contribution of bone marrow-derived cells to both liver fibrosis and repair. The mechanisms by which cells are trafficked from the bone marrow to the liver are complex; the stromal derived factor-1/CXC receptor 4 axis is central to this process. There are limited data in liver injury, but we will examine findings from the bone marrow transplantation literature and discuss their relevance to liver disease. Stromal derived factor-1 also has a role in endogenous liver stem cell accumulation. Some groups have already started infusing autologous bone marrow cells into patients with cirrhosis. We will review these trials in the context of the basic science that we have discussed, and we will consider targets for investigation in the future. Liver Transpl 16:118-129, 2010.
IntroductionNon-alcoholic fatty liver disease (NAFLD) is an important cause of cirrhosis. Cirrhosis can be considered as a state where disordered growth leads to inadequate repair and a risk of malignancy. We sought to study the growth characteristics of C3A cells in an in vitro model of NAFLD.MethodsC3A cells (well differentiated hepatoblastoma cells) were preconditioned for 72 h in control media, media containing oleate (which leads to steatosis, but not insulin resistance) or LPON media containing lactate (L), pyruvate (P), octanoate (O) and ammonia (N) (leading to steatosis, insulin resistance and increased reactive oxygen species). The cells were passaged and re-incubated in the appropriate media. Cells were harvested daily for cell counting and total protein estimation for 5 days. Cell cycle analysis and apoptosis estimation were performed on day 3.ResultsGrowth curves were established, showing by both cell counting and protein estimation that growth was significantly reduced in the NAFLD model (p< 0.0001) compared to control media and oleate (Abstract 002 Figure 1). Abstract PWE-002 Figure 1Growth curve. Cell cycle analysis showed that cells grown in LPON did not accumulate in G0/G1, but appeared to accumulate in S phase (Abstract 002 Figure 2). Cells grown in oleate cycled normally. There was an increase in apoptosis in both oleate and LPON groups (26.1 and 27.7% cells undergoing apoptosis, compared to 13.5% of control cells, p<0.0001). Abstract PWE-002 Figure 2Cell cycle analysis. ConclusionNAFLD-induced cells showed significantly impaired growth compared with both control and simple steatotic cells in this model. This was not wholly attributable to an increase in apoptosis, as there was a similar increase in apoptosis with steatosis. While simple fat accumulation increased apoptosis, there was in addition, impairment of cell growth in our NAFLD model, which may be due to formation of reactive oxygen species, causing DNA damage and cell cycle arrest.
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