Gut. 2007 May; 56(5): 716724.

Y N Kallis, Department of Medicine, St Mary's Hospital Campus, Imperial College, London, UK

M R Alison, Institute of Cell and Molecular Science, Queen Mary School of Medicine and Dentistry, London, UK

S J Forbes, Tissue Fibrosis and Remodelling Laboratory, MRC/University of Edinburgh Centre for Inflammation Research, Edinburgh, UK

Correspondence to: Professor S J Forbes MRC/University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; stuart.forbes@ed.ac.uk

Stem cells are present in a variety of organs including the bone marrow (BM). Their role is to replenish multiple mature differentiated cell types and thereby achieve longterm tissue reconstitution. Stem cells retain the capacity to generate progeny and renew themselves throughout life. Haematopoietic stem cells (HSCs) are the main stem cell population within the BM and give rise to all mature blood lineages via erythroid, myelomonocytic and lymphoid precursors. A second type of bone marrow stem cell (BMSC), the mesenchymal stem cell (MSC), forms stromal tissue and can give rise to cells of mesodermal origin.

A longstanding principle of cell biology has been that cell loss is reconstituted via stem cells resident within and specific to an organ. However, recent work suggests that this paradigm may not hold for all organs or all types of injury, and tissue damage may attract migratory stem cell populations, particularly those from the BM. This observation has caused considerable interest in the field of liver disease, where new strategies to restore hepatocyte number, augment liver function and counteract progressive organ fibrosis are required. This article will focus on the various relationships between BMSCs and liver disease. It will concentrate on the evidence from animal models and human studies that BMSCs may aid in the regeneration of liver cell populations and may also contribute to the pathogenesis of liver damage. It will discuss the potential to use BMSCs for therapeutic application and review the current status of clinical trials in patients with liver disorders.

The hepatic parenchyma is made up of hepatocytes and cholangiocytes. 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 a twothirds partial hepatectomy, most hepatocytes rapidly enter the cell cycle and undergo symmetrical mitosis. Liver cell mass can be restored via an average of less than two cell division cycles, albeit individual hepatocytes seem to have an intrinsic capacity for up to 70 doublings in serial transplantation experiments.1 At times of overwhelming cell loss, with longstanding iterative injury (eg, chronic viral hepatitis), or when hepatocyte replication is impeded (eg, replicative senescence of steatohepatitis), regeneration seems to occur via a second cell compartment.2,3 This compartment remains poorly defined and seems to arise from a less differentiated cell population within the terminal branches of the intralobular biliary tree the canals of Hering.4 In rodents these cells are called oval cells, but in humans they are more aptly named hepatic progenitor cells.5 Attempts to identify the originating stem cell are hampered by a paucity of specific cell surface markers.

Initial studies in humans suggested that some hepatocytes have a BM origin. Using Y chromosome tracking, a sparse number of hepatocytes seemed to be originating from the BM in male recipients of female orthotopic liver transplants, and in females who had received bone marrow transplantation (BMT) from male donors and thereafter developed liver disease.6,7 Similarly, other epithelial tissues, such as gut and skin, seemed to harbour cells of BM origin.8 Investigators then turned to an animal model of hereditary type I tryosinaemia, the fumarylacetoacetate hydrolase knockout mouse (FAH(/)), in which it seemed that this potentially fatal enzyme deficiency could be rescued through repopulation of the abnormal liver by BM cells derived from wildtype donors. The implication was that stem cells could cross conventionally demarcated lineage boundaries through a process termed transdifferentiation or stem cell plasticity, leading researchers to question the longheld tenets of cell biology. With time, it became apparent that these initial observations were difficult to reproduce, and later elegant studies in the same FAH(/) mouse model conclusively showed that monocytehepatocyte fusion was the explanation for the restored normal phenotype to the FAHdeficient liver, in which hepatocytes formed by fusion expanded rapidly owing to a considerable survival advantage.9,10

Unfortunately, in the absence of a strong selective pressure, it seems that stable longterm engraftment of BMderived parenchymal cells is unusual. In rats given inhibitors of hepatocyte replication (eg, dgalactosamine, retrorsine or 2acetylaminofluorene), if subjected to a regenerative stimulus such as a partial hepatectomy, BMderived oval cell engraftment can rapidly decrease with time to <1%.11 In the hepatitis B surface antigen transgenic mouse, the BM contributed to hepatocyte repopulation through cell fusion, but only at a very modest rate. In this model, constitutive HBsAg expression induces chronic lowgrade hepatocyte turnover with nodule formation, and inhibition of hepatocyte replication with retrorsine provokes an oval cell response. Here, the contribution from BMderived cells to hepatocyte repopulation waned to just 1.6% by 6months, presumably owing to lack of a sustained selection advantage.12 Likewise, when human HSCs were transplanted into carbon tetrachloride (CCl4)damaged nonobese diabetes/severe combined immune deficiency (NOD/SCID) mice, donorderived hepatocytes expressing mRNA for human albumin and 1 antitrypsin were found in the liver. These hepatocytes occurred through cell fusion, but the phenotype of the chimaeric cells was variable and donorderived genetic material was lost over time.13 When human cord blood, a rich source of progenitor cells, was transplanted into sublethally irradiated NOD/SCID mice, a contribution to the hepatocyte population of only 0.01% was found in the undamaged liver, reportedly through transdifferentiation.14 However, a subsequent study using human cord blood cells again demonstrated only low levels of hepatocyte repopulation even after CCl4induced or hepatocyte growth factor (HGF)induced regeneration. Here the cells were chimaeric for both human and mouse antigens, suggesting that cell fusion rather than transdifferentiation had occurred.15

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