Therapeutic Strategies For Liver Diseases Research Articles

Evidence of cell-fate conversion from hepatocytes to cholangiocytes in the injured liver

Recently, it has been suggested that hepatocytes can potentially convert their fate into that of cholangiocytes when the liver receives an injury. This review concisely summarizes these new findings, especially those obtained in studies using cell-lineage tracing methods. Recent advances in technologies using mutant mice with a tamoxifen-inducible Cre/loxP system have allowed heritable labeling of a particular type of cell and enabled us to follow the fate of their progeny. This is generally known as 'genetic lineage-tracing', and has been applied in various studies that require tracking of the fate of cells in living mice. Previous studies using these methods have revealed that hepatocytes themselves can give rise to cholangiocytes through Notch-mediated cell-fate conversion from hepatocytes to cholangiocytes in injured liver tissue and at the onset of liver cancer. Intensive studies using in-vivo genetic lineage-tracing approaches have provided new insights into the nature of cellular identity and plasticity in the liver, which will contribute to the development of new therapeutic strategies for liver diseases.

MBSJ MCC Young Scientist Award 2012 Liver regeneration: a unique and flexible reaction depending on the type of injury.

The liver can be thought of as a mysterious organ, because it has an elegant regenerative capability. This phenomenon has been well known since ancient times and is already applied to medical treatments for severe hepatic disorders by transplanting portions of liver received from living donors. However, it was not until quite recently that the mechanism underlying the principle of liver regeneration was investigated more deeply. Recent advances in the technologies for characterizing cell properties and examining the molecular nature of cells are enabling us to understand what occurs in the regenerating liver. After acute liver damage, hepatocytes actively proliferate in response to external stimulation by humoral factors. However, in the chronically injured liver, hepatocytes cannot proliferate well, but biliary cells appearing after chronic liver damage form primitive ductules around portal veins of the liver. These biliary cells may have a multiple origin, including hepatocytes, and contain progenitor cells giving rise to both hepatocytes and biliary cells, or represent cells that can be directly converted into hepatocytes. Although liver regeneration is more complicated than we had thought, unremitting efforts by researchers will certainly connect the numerous findings obtained in basic research with the development of new therapeutic strategies for liver diseases.

Reversal of vasohibin-driven negative feedback loop of vascular endothelial growth factor/angiogenesis axis promises a novel antifibrotic therapeutic strategy for liver diseases

Reversal of vasohibin-driven negative feedback loop of vascular endothelial growth factor/angiogenesis axis promises a novel antifibrotic therapeutic strategy for liver diseases

Hepatocytes, Rather than Cholangiocytes, Can Be the Major Source of Primitive Ductules in the Chronically Injured Mouse Liver

The proliferation of biliary lineage cells in chronic liver diseases, which leads to formation of primitive ductules in portal areas of the hepatic lobule, may be important not only for liver regeneration, but also for initiation of liver cancer. Thus, understanding how these primitive ductular cells emerge and proliferate in chronically injured liver holds promise for development of therapeutic strategies for liver diseases. However, the origin of these primitive ductular cells remains controversial. Here, we use a method for genetic lineage tracing to determine the origin of cells that form primitive ductules in a mouse model of chronic liver injury. Our results show that hepatocytes, rather than cholangiocytes, are the major source of cells for the primitive ductules formed in response to chronic liver damage. Moreover, activation of the Notch-Hes1 signaling axis is important for conversion of hepatocytes into primitive ductular cells in chronically injured liver. These findings should be valuable in elucidating the mechanism of liver regeneration associated with the fate-conversion of hepatocytes and in developing therapeutic strategies for liver diseases.

Hepatocyte Growth Factor Prevents Lipopolysaccharide-Induced Hepatic Sinusoidal Endothelial Cell Injury and Intrasinusoidal Fibrin Deposition in Rats

Background.Acute endotoxemia is known to cause activation of Kupffer cells as well as serious injury in parenchymal and nonparenchymal cells in the liver. We have recently shown that a continuous recombinant hepatocyte growth factor (rHGF) supply prevents lipopolysaccharide (LPS)-induced liver injury in rats. As an attempt to elucidate the mechanism, here we investigate the cytoprotective effect of rHGF on sinusoidal endothelial cells (SECs) in LPS-induced liver injury in rats.Materials and methods.In order to supply rHGF continuously to the liver, syngenic rat fibroblasts genetically modified to secret rat rHGF were implanted in the spleen. Fourteen days after cell implantation, we injected LPS intravenously and evaluated SEC damage histologically and blood chemically.Results.Phosphotungstic acid–hematoxylin staining revealed that rHGF treatment greatly attenuated intrasinusoidal LPS-induced fibrin deposition. The ultrastructural changes in SECs caused by LPS administration in control rats were barely detectable in rHGF-treated rats. Blood chemical analyses showed that rHGF potently suppressed the LPS-induced increase in serum hyaluronic acid and transaminase levels.Conclusions.Our results indicate an important role for HGF in SEC protectionin vivoand would suggest a novel therapeutic strategy for liver diseases with SEC injury.