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Liver repopulation with cell transplantation: Provides hope of life for patients with end stage liver diseases.

Liver transplant has been at the forefront of clinical regenerative medicine. The remarkable ability of the liver to regenerate and the advent of living donor liver transplant came as a boon for patients with end stage liver disease.

In recent times, liver donor shortages have fueled clinically viable alternative for liver repopulation by cell transplantation. Researchers hypothesized that cellular therapy should be able to “repair” or “regenerate” a failing liver or be able to augment native liver regeneration after liver resections or living donor liver transplant surgeries.

Initial attempts at cellular therapy were found beneficial in patients with end stage liver disease or with certain genetic and metabolic liver disorders when infused with primary hepatocytes via the portal vein disease with some beneficial effect. But, improvements in liver function were not long-term. This was presumed to be because adult liver cells, the hepatocytes have very minimal proliferative activity within the normal liver. Further, harvesting adult liver cells were also very difficult to preserve and have limited application in conditions that require liver repopulation.

On the other hand, stem cells give rise to somatic stem cells that differentiate further into multipotent tissue-specific stem cells, which further give rise to progenitor cells that subsequently proliferate and differentiate into mature somatic phenotypes that comprise an organ mass. Hence, human hepatic stem cells became viewed as a new alternative source of human hepatocytes. To date, several kinds of stem cells have been investigated for their therapeutic feasibility and clinical potential in liver disease.

Human hepatic stem cells may be separated from fetal and postnatal livers and could give rise to differentiated hepatocytes in vitro and more mature hepatocytes in vivo, providing an opportunity to overcome conditions that require liver repopulation such as acute and chronic liver injuries. Liver stem/progenitor cells, thus, get activated to proliferate and differentiate when there is demand for hepatocytes.

Developing such a cell line from human embryonic stem cells or from other human stem cell sources would provide a valuable tool for cell-based therapeutics. Specific marker expression profiles that can be used to identify and isolate human hepatic stem cells from human primary fetal liver cells are still unclear.

Various studies have reported that cells from the bone marrow are released into the circulation, migrate to the liver and differentiate into hepatocytes. However, the extent to which this occurs and the mechanisms involved remain highly controversial.

Latest research has identified cells in the fetal, neonatal, and adult liver with stem-cell properties. Cell lines have also been established, including 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 equipment and technology, except for rat fetal liver stem/progenitor cell that is able to produce substantial long-term replacement and function.

More studies are still evaluating the advances in the field of liver cell therapy. The focus for liver repopulation with cell transplantation is to find the necessary conditions under which cells and cell lines derived from embryonic stem cells, fetal liver, or adult liver can be expanded in culture and successfully repopulate the liver under conditions that will be clinically acceptable.

Remarkable advancements in liver regenerative medicine continue with ongoing basic science advancements as well as standardized and carefully designed clinical trials to bridge the gaps and make these new cell therapies a reality for patients with inborn metabolic disorders, as well as chronic liver diseases of various etiologies.