ReviewLiver stem cells and model systems for liver repopulation
Section snippets
General concepts of stem and progenitor cells
Embryonic stem cells originate from the inner cell mass of the mammalian blastocyst and are totipotent [1]. Under certain conditions, these cells can be propagated in culture as stable, undifferentiated pluripotent stem cell lines. During development, embryonic stem cells give rise to somatic stem cells (reviewed in Refs. [2], [3]). Somatic stem cells differentiate further into multipotent tissue stem cells which have been identified and isolated from the neural crest, bone marrow and central
Stem cells during liver embryologic development
Classical embryological studies have traced the proliferation and differentiation of endodermal stem cells into the hepatocytic and bile ductular cell lineages during normal liver development [15], [16], [17], [18], [19], [20]. This process begins on embryonal day (ED) 8.5 in the mouse with proliferation of undifferentiated endodermal cells of the ventral foregut and their migration into the septum transversum, where they come into contact with mesenchymal cells (see Fig. 1). At this point,
Liver regeneration
The ability of the liver to regenerate is a property that is unique among solid organs in mammalian species. Following two-thirds partial hepatectomy (PH), there is compensatory growth by the remaining liver, resulting in restoration of the total parenchymal cell number and mass within 1–2 weeks [9], [10]. This process is not really regeneration, because the lost anatomic structures are not replaced, but the remaining tissue expands to its original mass by proliferation of preexisting cells.
Are there stem cells in the adult liver?
The existence of stem cells in the adult liver, a highly controversial topic [41], was postulated initially more than 40 years ago by Wilson and Leduc [42]. This was based on studies in rodents in which it appeared that cells in the distal cholangioles of the bile ducts were responsible for restoration of liver mass after dietary injury. At that time, it was also established that bile duct epithelial cells and hepatocytes are of common embryologic origin, derived from hepatoblasts emanating
‘Oval cells’ as hepatocyte progenitors
The first study demonstrating the existence of small undifferentiated epithelial cells in the adult liver was reported by Farber [43], who treated rats with different carcinogens, such as ethionine, 2-acetylaminofluorene (2-AAF) and 3-methyl-4-dimethylaminobenzene. In these studies, Farber noted proliferation of epithelial cells in the periportal region with scant basophilic cytoplasm and an oval-shaped, pale blue, homogeneously stained nucleus, which he termed ‘oval cells’. Ultimately, he
Other models of ‘oval cell’ activation
Another rat model showing activation of liver progenitor (‘oval’) cells is d-galactosamine (D-galN)-induced liver injury. A single i.p. dose of D-galN (70–80 mg/100 g body weight) traps uridine nucleotides and UDP-glucose in hepatocytes, which leads to inhibition of RNA and protein synthesis and acute hepatocytic necrosis [53]. During uridine triphosphate deprivation, residual hepatocytes cannot proliferate and survival of the animal depends upon activation of immature hepatic epithelial cells
Relationship of ‘oval cells’ to the canals of Hering
The canals of Hering were original identified by their namesake in 1866 as luminal channels linking the hepatocyte canalicular system to the biliary tree [77]. Transmission electron microscopy has identified small undifferentiated epithelial cells lining these channels [78], [79]. These cells are often in direct physical continuity with hepatocytes at one membrane boundary and bile duct cells at another boundary and together they form duct-like structures enclosing a lumen (i.e. the canal).
Studies with liver-derived ‘oval cells’ lines
Permanent lines of liver epithelial cells have been established that have characteristics similar to ‘oval cells’ and are thought to be derived from epithelial progenitor cells [88], [89], [90], [91], [92]. The best characterized and most extensively studied of these cell lines is that derived by Grisham and coworkers, WB-F344 [90]. When WB-F344 cells were transduced with a β gal gene and then transplanted into the liver of syngeneic rats, the cells integrated into the hepatic plates acquired
Cell transplantation models for liver repopulation
Initial studies demonstrated that after transplantation to the spleen, hepatocytes migrate to the liver and become functionally incorporated into the parenchymal plates [100], [101], [102]. Transplanted hepatocytes were localized primarily in the periportal regions and it was quite surprising that these rather large cells (25–30 μm diameter) could actually cross the liver sinusoids. However, transplanted hepatocytes do not repopulate the normal liver significantly after two-thirds PH [103].
Retrorsine/PH model for liver repopulation
In both of the above models, a unique combination of experimental conditions in the host environment permits repopulation of the liver by transplanted hepatocytes: (1) the liver is under a constant state of massive injury/regeneration; and (2) the transplanted cells have an enormous selective advantage for survival compared to host hepatocytes. However, both uPA transgenic mice and FAH null mice are perinatal lethal and comparable conditions will be found only rarely in humans. An alternative
Transplantation of ‘oval cells’, cell lines and fetal liver epithelial (stem/progenitor) cells
With the development of an effective hepatic cell transplantation and detection system, it was hoped that liver repopulation could be achieved by transplanting hepatic progenitor (‘oval’) cells or cell lines. Since these cells or cell lines would be expected to have a higher proliferative rate or capacity than mature hepatocytes and should have the ability to differentiate into both hepatocytes and bile duct cells, it was hoped that effective liver repopulation and generation of complete new
Plasticity and the role of the liver microenvironment
As evident from recent studies in brain, bone marrow, liver and pancreas, somatic cells exhibit considerable flexibility in their gene expression properties and cells derived from one organ can differentiate into cells of another organ after their engraftment into the latter site (see Fig. 3). This property is referred to as plasticity. In the liver, when fetal liver stem/progenitor cells engraft in the portal space, they differentiate into bile duct cells and when they engraft into the
Hematopoietic stem cells and liver repopulation
Until recently, it was thought that stem cells in adult organs (somatic or tissue-determined stem cells) were restricted to a single embryonic germ layer, but recent studies with hematopoietic and brain stem cells indicate differentiation across germ cell layers [128], [129], [130], [131], [132], [133], [134], [135], [136], [137]. As part of these studies, Petersen et al. [132] and Theise et al. [133] transplanted either crude bone marrow or purified hematopoietic stem cells into lethally
Enriched populations of liver stem/progenitor cells
The first studies reporting enrichment of fetal liver stem/progenitor cells were those of Reid and coworkers [97] using panning and fluorescence activated cell sorting methods with monoclonal antibodies reacting with cell surface proteins expressed on oval cells and bile duct epithelial cells. However, even today, specific selection markers for fetal liver stem/progenitor cells have not been identified. Fetal liver cells have been sorted by Suzuki et al. [138] for those that are positive for
Summary
During the past decade, it has become clear that the mammalian liver contains stem/progenitor cells. These cells are derived embryologically from the foregut endoderm (see schematic diagram, Fig. 4) and seed the bone marrow, giving rise to hematopoietic stem cells. They also generate undifferentiated epithelial cells which are maintained in the canals of Hering, situated at the terminal webs of the bile ductules. Both hematopoietic stem cells and canals of Hering cells can give rise to hepatic
Acknowledgements
The authors would like to thank Anna Caponigro and Emily Bobe for secretarial assistance in preparing this manuscript and our many students and postdoctoral fellows for their contributions to studies from our laboratory cited in this review.
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