Elsevier

Journal of Hepatology

Volume 36, Issue 4, April 2002, Pages 552-564
Journal of Hepatology

Review
Liver stem cells and model systems for liver repopulation

https://doi.org/10.1016/S0168-8278(02)00013-2Get rights and content

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.

First page preview

First page preview
Click to open first page preview

References (141)

  • N Omori et al.

    Partial cloning of rat CD34 CDNA and expression during stem cell-dependent liver cell regeneration in adult rats

    Hepatology

    (1997)
  • E Laconi et al.

    Long term, near total liver replacement by transplantation of isolated hepatocytes

    Am J Pathol

    (1998)
  • G.J Gordon et al.

    Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response

    Am J Pathol

    (2000)
  • L Yavorkovsky et al.

    Participation of small intra portal stem cells in the restitutive response to periportal injury induced by allyl alcohol

    Hepatology

    (1995)
  • O Yasui et al.

    Isolation of oval cells from Long-Evans Cinnamon rats and their transformation into hepatocytes in vivo in the rat liver

    Hepatology

    (1997)
  • M.S Rao et al.

    Almost total conversion of pancreas to liver in the adult rat: a reliable model to study transdifferentiation

    Biochem Biophys Res Commun

    (1988)
  • G.J Abelev

    Alpha-fetoprotein in ontogenesis and its association with malignant tumors

    Adv Cancer Res

    (1971)
  • S Paku et al.

    Origin and structural evolution of the early proliferating oval cells in rat liver

    Am J Pathol

    (2001)
  • S Sell

    Heterogeneity and plasticity of hepatocyte lineage cells

    Hepatology

    (2001)
  • J.S Sandhu et al.

    Stem cell properties and repopulation of the rat liver by fetal liver epithelial progenitor cells

    Am J Pathol

    (2001)
  • G.M Williams et al.

    Isolation and long-term cell culture of epithelial-like cells from rat liver

    Exp Cell Res

    (1971)
  • M.-S Tsao et al.

    A diploid epithelial cell line from normal adult rat liver with phenotypic properties of oval cells

    Exp Cell Res

    (1984)
  • C.P Plescia et al.

    Genomic expression analysis implicates Wnt signaling pathway and extracellular matrix alterations in hepatic specification and differentiation of murine hepatic stem cells

    Differentiation

    (2001)
  • J.A Thomson et al.

    Embryonic stem cell lines derived from human blastocyst

    Science

    (1998)
  • A.D Whetton et al.

    Homing and mobilization in the stem cell niche

    Trends Cell Biol

    (1999)
  • G.B Pierce et al.
  • C.S Potten et al.

    Stem cells: attributes, cycles, spirals, pitfalls and uncertainties: lessons for and from the crypt

    Development

    (1990)
  • G.K Michalopoulous et al.

    Liver regeneration

    Science

    (1997)
  • E.P Sangren et al.

    Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene

    Cell

    (1991)
  • J Rhim et al.

    Replacement of diseased mouse liver by hepatic cell transplantation

    Science

    (1994)
  • K Overturf et al.

    Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I

    Nat Genet

    (1996)
  • K Overturf et al.

    Serial transplantation reveals the stem-cell like regenerative potential of adult mouse hepatocytes

    Am J Pathol

    (1997)
  • A.M DuBois

    The embryonic liver

  • J.W Wilson et al.

    Histogenesis of the liver

    Ann N Y Acad Sci

    (1963)
  • N.M Le Douarin

    An experimental analysis of liver development

    Med Biol

    (1975)
  • S Casio et al.

    Hepatocyte differentiation initiates during endodermal-mesodermal interactions prior to liver formation

    Development

    (1991)
  • N Shiojiri et al.

    Cell lineages and oval cell progenitors in rat liver development

    Cancer Res

    (1991)
  • K.S Zaret

    Molecular genetics of early liver development

    Annu Rev Physiol

    (1996)
  • J Jung et al.

    Initiation of mammalian liver development from endoderm by fibroblast growth factors

    Science

    (1999)
  • R.R Meehan et al.

    Pattern of serum protein gene expression in mouse visceral yolk sac and fetal liver

    EMBO J

    (1984)
  • L.B Tee et al.

    Dual phenotypic expression of hepatocytes and bile ductular markers in developing and preneoplastic rat liver

    Carcinogenesis

    (1996)
  • N Fausto

    Hepatocyte differentiation and liver progenitor cells

    Curr Opin Cell Biol

    (1990)
  • S Thorgeirsson

    Hepatic stem cells and liver regeneration

    Fed Am Soc Exp Biol J

    (1996)
  • D.C Hixson et al.

    Antigenic phenotypes common to rat oval cells, primary hepatocellular carcinoma and developing bile ducts

    Carcinogenesis

    (1997)
  • N Marceau et al.

    The role of biopotential progenitor cells in liver ontogenesis and neoplasia

  • G.D Block et al.

    Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGFβ in a chemically defined (HGM) medium

    J Cell Biol

    (1996)
  • L Germain et al.

    Biliary epithelial and hepatocytic cell lineage relationships in embryonic rat liver as determined by the differential expression of cytokeratins, α-fetoprotein, albumin, and cell surface exposed components

    Cancer Res

    (1988)
  • D.C Hixson et al.

    An antigenic portrait of the liver during carcinogenesis

    Pathobiology

    (1990)
  • L Germain et al.

    Promotion of growth and differentiation of rat ductular oval cells in primary culture

    Cancer Res

    (1988)
  • R Van Eyken et al.

    Intrahepatic bile duct development in the rat: a cytokeratin-immunohistochemical study

    Lab Invest

    (1988)
  • Cited by (109)

    • Resident Liver Stem Cells

      2023, Resident Stem Cells and Regenerative Therapy: Sources and Clinical Applications, Second Edition
    • Developmental Biology of Stem Cells

      2017, Fetal and Neonatal Physiology, 2-Volume Set
    View all citing articles on Scopus
    View full text