Forbes Stuart
(Edinburgh University, UK)
Liver disease is the fifth most common cause of death in the UK. At present the only effective treatment for advanced cirrhosis is liver transplantation. The use of transplantation is significantly limited by organ availability and the fact that for other medical reasons not every patient is a suitable recipient. It is estimated that over the next 6-10 years there will be 500% increase in the need for liver transplantation in the UK. Even at present levels the need for liver transplantation markedly outweighs the number of donor organs available for liver transplant and unfortunately approximately 15% of patients on the waiting list for liver transplant will die before a suitable organ is available. Alternatives ways to regenerate the liver are urgently required.
The hepatic parenchyma is made up of hepatocytes. Unlike other organs such as the gut, liver cell mass is restored primarily through division of the majority of mature hepatocytes and not via a dedicated stem cell population. After a regenerative stimulus, such as hepatic resection, hepatocytes rapidly enter the cell cycle and undergo mitosis. At times of severe or chronic liver damage regeneration occurs via a second cell compartment. This compartment remains poorly defined and seems to arise from the terminal branches of the biliary tree- the canals of Hering. In rodents these cells are called “oval cells” but in humans they are named hepatic progenitor cells (HPCs). Recently it was suggested that the bone marrow (BM) was an additional source of hepatocytes and oval cells within the liver. The implication was that stem cells could cross conventionally-demarcated lineage boundaries through a process termed transdifferentiation or stem cell plasticity.
We have systematically studied the intra and extra-hepatic sources of liver cell replacement in mouse models of chronic liver injury. Our results indicate that parenchymal regeneration occurs principally through hepatocyte replication. The BM very rarely contributed to hepatocyte regeneration and, when seen this was largely due to cell fusion between indigenous hepatocytes and donor BM. However, BM cells largely contribute to non-parenchymal cells and the fibrotic cell populations within the liver. These BM-derived myofibroblasts originate largely from the BM’s mesenchymal stem cells and is therefore a potential therapeutic target in liver fibrosis. The BM also supplies “scar associated macrophages” that populate the areas of liver fibrosis. These macrophages are of interest as they help stimulate liver fibrosis during damage but can also help the resolution of scar tissue during the resolution of liver fibrosis.
Various fractions of BM have been used for “BM stem cell therapy” in rodent models of liver injury, including endothelial progenitor cells (EPCs) and these seem to be effective at provoking a reduction in liver fibrosis and stimulating liver regeneration. To date there are only a handful of clinical trials which have looked at the effect of autologous “BM stem cell therapy” for liver disease, all of which are small-scale, uncontrolled feasibility studies. These studies have looked at a variety of scenarios. In patients undergoing hepatectomy for cancer, accelerated hepatic regeneration was seen in patients after the infusion of autologous CD133+ BM cells. Other studies have examined haematopoietic stem cell therapy for liver cirrhosis. Although uncontrolled, preliminary results from these studies are encouraging.
An encouraging source of stem cell derived hepatocytes are embryonic stem (ES) cells. These have been shown to adopt a hepatocyte phenotype in vitro. These cells may find use in bio-artificial livers, for hepatocyte transplantation, or for drug testing as currently there is no reliable source of human hepatocytes.
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