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Abstract
End stage liver disease (ESLD) is the final stage of acute or chronic liver damage and is associated with liver failure. ESLD can develop rapidly, over days or weeks (acute and sub-acute liver failure, respectively), or gradually, over months or years (chronic liver failure). Cirrhosis represents the final common pathological outcome for the majority of chronic liver diseases. Most patients with cirrhosis die from one or more clinical complications including ascites, hepatic encephalopathy, and variceal hemorrhage.
Currently, liver transplantation is the most effective therapy for patients with ESLD. However, its potential benefits are hampered by many drawbacks, such as the relative shortage of donors, operative risk, post-transplant rejection, recidivism of the pre-existing liver disease, and high costs.
Liver transplantation has been the most effective therapy for the patients with advanced liver diseases. Unfortunately, most patients are unable to obtain transplantation due to the limited availability of donor livers. Over 10% of patients die while waiting for liver transplantation. Among the fortunate patients who received liver transplants, the survival rate has been 94% at 3 months, 88% at 1 year and 79% at 3 years. Thus, it is of great interest to search for an effective alternate to treat this type of life-threatening disease. Recently, stem cell-based therapy has shown promising benefit on animal models and some clinical patients.
Stem cell therapy sounds particularly attractive for its potential to support tissue regeneration requiring minimally invasive procedures with few complications. This field of research, which represents the ground from which the new discipline of “regenerative medicine” has germinated, has rapidly developed in recent years, arising great interest among scientists and physicians, and frequently appearing in newspapers headlines touting miracle cures, but arising ethical crises as well.
Considerable advances have been made in identifying cells in the fetal, neonatal and adult liver with stem cell properties. Cell lines have also been established, including ES cells, fetal liver cells, and oval (progenitor) cells that also exhibit stem cell properties and differentiate into hepatocytes and/or bile ducts in vitro and in vivo. However, all of these cells and cell lines have shown only limited repopulation of the normal liver at the current state-of-the-art, except for rat fetal liver stem/progenitor cells that produce substantial longterm replacement and function. In order to further advance the field of liver cell therapy, it will be necessary to find conditions under which cells and cell lines derived from ES, fetal liver or adult liver, can be expanded in culture and successfully repopulate the liver under conditions that will be clinically acceptable. Such cell therapy can be readily visualized for treatment of inborn metabolic disorders, as well as chronic liver diseases of various etiologies.
Further work is required before we can be confident that stem cells can cure liver disease. Only conclusive evidence of using Stem cell therapy potentiating hepatocyte functions for temporary correction of an irreversible hepatic disease mainly used prior to transplantation. Although there are many promising laboratory studies, there are only a handful of disease models that have been used to test stem cell correction of liver disease and there is an urgent need to develop more clinically relevant models.
Our understanding of the complex nature of liver regeneration and the role of the various stem cell compartments in liver repair has reached new levels. However, we are only now beginning to understand that there is unlikely to be one stem cell therapy for all liver diseases.
There are still significant clinical hurdles that will need to be overcome if stem cell therapy is to reach the full potential that its champions have anticipated. The prizes are rich but the journey is long, and we might just uncover some unexpected treasures of liver biology in the process.