EpCAM in hepatocytes and their progenitors
Authors: Olivier Gires
Journal: Journal of Hepatology (2011)

COMMENTARY ON: Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans. Yoon SM, Gerasimidou D, Kuwahara R, Hytiroglou P, Yoo JE, Park YN, Theise ND. Hepatology 2011 Mar;53(3):964–973. http://www.ncbi.nlm.nih.gov/pubmed/21319194 Liver deterioration as a consequence of injury and inflammation becomes counteracted by active organogenic regeneration. The cellular origin of regeneration depends on the duration of disease. Acute and early stages of chronic hepatitis result in the transient proliferation of organ-resident hepatocytes. Chronic and long-lasting hepatitis exhausts this proliferative potential and induces senescence. Thereafter, regeneration is conducted by tissue stem cells via transit amplifying and differentiating cells. Human liver stem cells in chronic hepatitis manifest as ductular reactions (DR), which represent potential intrahepatic, hepatobiliary tissue stem cells. Yoon et al. reported on DR being tissue stem/progenitor compartments and regenerative areas [[1]Yoon S.M. Gerasimidou D. Kuwahara R. Hytiroglou P. Yoo J.E. Park Y.N. et al.Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans.Hepatology. 2011; 53: 964-973Crossref PubMed Scopus (124) Google Scholar], which were characterised by strong cytoplasmic staining of epithelial cell adhesion molecule EpCAM. Along with hepatocellular differentiation, cells increasingly shifted EpCAM localisation from cytoplasmic to membranous. Transit-amplifying cells were characterised by intermediate EpCAM expression, proliferation, and telomere length, ranging between DR cells and differentiated EpCAM-negative hepatocytes (Fig. 1A). Data by Yoon et al. clearly speak in favour of a hierarchically structured regeneration of the liver based on differentiation processes, rather than a transient proliferation of pre-existing hepatocytes during late stages of the disease. The EpCAMhigh phenotype in bipotential hepatoblast precursors and changes of EpCAM expression along with hepatocellular differentiation traits are of utmost interest in light of the reported adhesive, signalling, and proliferative properties of EpCAM in cancer, normal progenitor cells, and in tumour-initiating cells [[2]Munz M. Baeuerle P.A. Gires O. The emerging role of EpCAM in cancer and stem cell signaling.Cancer Res. 2009; 69: 5627-5629Crossref PubMed Scopus (415) Google Scholar]. EpCAM is a pan-epithelium marker, which is expressed in a great variety of differentiated epithelia. Squamous epithelia mostly lack EpCAM, except for cells of the basal layer, which represent the less differentiated cells with residual proliferation capacity. Embryonic stem cells (ES), induced-pluripotency stem cells, and tissue progenitors of various organs including liver, kidney, mammary gland, and hair follicle highly express EpCAM at plasma membranes, and downregulate it once organo- and morphogenesis is completed [3Chen H.F. Chuang C.Y. Lee W.C. Huang H.P. Wu H.C. Ho H.N. et al.Surface marker epithelial cell adhesion molecule and E-cadherin facilitate the identification and selection of induced pluripotent stem cells.Stem Cell Rev. 2011; 7: 722-735Crossref PubMed Scopus (49) Google Scholar, 4Gonzalez B. Denzel S. Mack B. Conrad M. Gires O. EpCAM is involved in maintenance of the murine embryonic stem cell phenotype.Stem Cells. 2009; 27: 1782-1791Crossref PubMed Scopus (89) Google Scholar, 5Lu T.Y. Lu R.M. Liao M.Y. Yu J. Chung C.H. 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Proteolytic cleavage generates an intracellular signalling domain (EpICD), which uses components of the Wnt signalling pathway (i.e. FHL2, β-catenin, Lef-1), activates promoters of stemness genes including c-Myc, Sox2, Nanog, Oct4, and KLF4 [5Lu T.Y. Lu R.M. Liao M.Y. Yu J. Chung C.H. Kao C.F. et al.Epithelial cell adhesion molecule regulation is associated with the maintenance of the undifferentiated phenotype of human embryonic stem cells.J Biol Chem. 2010; 285: 8719-8732Crossref PubMed Scopus (102) Google Scholar, 11Maetzel D. Denzel S. Mack B. Canis M. Went P. Benk M. et al.Nuclear signalling by tumour-associated antigen EpCAM.Nat Cell Biol. 2009; 11: 162-171Crossref PubMed Scopus (539) Google Scholar] and is required for proliferation of EpCAM-positive cells [11Maetzel D. Denzel S. Mack B. Canis M. Went P. Benk M. et al.Nuclear signalling by tumour-associated antigen EpCAM.Nat Cell Biol. 2009; 11: 162-171Crossref PubMed Scopus (539) Google Scholar, 12Denzel S. Maetzel D. Mack B. 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Thus, EpCAMhigh in hepatocellular progenitor/stem cells potentially empowers them with pluripotency and proliferative traits, while declining expression in transit-amplifying cells might be sufficient to disconnect cells from multipotency programs but still drive transient proliferation. Differentiated hepatocytes do not or barely express EpCAM and will accordingly lack signals related to both, stemness and proliferation. Cytoplasmic localisation of EpCAM in hepatocellular progenitors as reported by Yoon et al. is, however, intriguing. EpCAM expression in normal, cancer, and stem cells was predominantly or even exclusively observed at the plasma membrane, where signalling initiates [11Maetzel D. Denzel S. Mack B. Canis M. Went P. Benk M. et al.Nuclear signalling by tumour-associated antigen EpCAM.Nat Cell Biol. 2009; 11: 162-171Crossref PubMed Scopus (539) Google Scholar, 12Denzel S. Maetzel D. Mack B. Eggert C. Barr G. Gires O. Initial activation of EpCAM cleavage via cell-to-cell contact.BMC Cancer. 2009; 9: 402Crossref PubMed Scopus (65) Google Scholar]. An alternative scenario is conceivable in which EpCAM signalling towards multipotency and proliferation initiates within DR cells at intracellular membranes, while its presence at plasma membranes rather associates with adhesive functions (Fig. 1). This would allow for balanced regulation of proliferation, differentiation, and cell adhesion along differentiation cascades from DR to mature hepatocytes. In this respect, assessment of the subcellular localisation of the signalling domain of EpCAM (EpICD) in the various cell types of chronically injured liver would shed light on these open questions and provide experimental evidence for or against this hypothesis. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.