Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans

Abstract

Epithelial cell adhesion molecule (EpCAM) is a surface marker on human hepatic stem/ progenitor cells that is reported as absent on mature hepatocytes. However, it has also been noted that in cirrhotic livers of diverse causes, many hepatocytes have EpCAM surface expression; this may represent aberrant EpCAM expression in injured hepatocytes or, as we now hypothesize, persistence of EpCAM in hepatocytes that have recently derived from hepatobiliary progenitors. To evaluate this concept, we investigated patterns of EpCAM expression in hepatobiliary cell compartments of liver biopsy specimens from patients with all stages of chronic hepatitis B and C, studying proliferation, senescence and telomere lengths. We found that EpCAM(1) hepatocytes were rare in early stages of disease, became increasingly prominent in later stages in parallel with the emergence of ductular reactions, and were consistently arrayed around the periphery of cords of keratin 19(1) hepatobiliary cells of the ductular reaction, with which they shared EpCAM expression. Proliferating cell nuclear antigen (proliferation marker) and p21 (senescence marker) were both higher in hepatocytes in cirrhosis than in normal livers, but ductular reaction hepatobiliary cells had the highest proliferation rate, in keeping with being stem/progenitor cell-derived transit amplifying cells. Telomere lengths in EpCAM(1) hepatocytes in cirrhosis were higher than EpCAM(2) hepatocytes (P < 0.046), and relatively shorter than those in the corresponding ductular reaction hepatobiliary cells (P 5 0.057). Conclusion: These morphologic, topographic, immunophenotypic, and molecular data support the concept that EpCAM(1) hepatocytes in chronic viral hepatitis are recent progeny of the hepatobiliary stem/progenitor cell compartment through intermediates of the transit amplifying, ductular reaction hepatobiliary cells. (HEPATOLOGY 2011;53:964-973)

Keratin 19 Epithelial Patterns in Cirrhotic Stroma Parallel Hepatocarcinogenesis

“…6,7,9,11,74 -78 The observed progressive alterations in the ductular compartment of premalignant and malignant hepatocellular lesions also indicate a substantial change in the otherwise prototypic ductular response to chronic injury (ie, cirrhosis). [1][2][3]79 In addition to exhaustion of the K19-based stem cell niche, 32,33,56,79,80 our findings emphasize alterations of an intricate relationship between intralesional and extralesional compartments as hepatocarcinogenesis progresses. Notwithstanding the known relation of intranodular mesenchymal elements of HCC (eg, reticulin pattern, unpaired arteries, sinusoidal capillarization, and vascular and extranodular stromal invasion 9,10,76,77 ), as well as imaging applications that use altered vascular biology in HCC for detection via dynamic methods, 81 changes in the nonhepatocellular epithelial compartment remain largely unexplored, 7,8,16,45 and our findings provide a morphologic starting point to examine whether loss of perinodular DR is a bystanding or contributing factor in progressive stages of hepatocarcinogenesis.…”

Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals

“…As illustrated in the results' section, the expression of known hepatic progenitor cell markers was upregulated upon sequential exposure to liver-specific hepatogenic growth factors and cytokines. These markers included EPCAM, a surface marker of both human hepatic progenitor cells [48] and newly-derived hepatocytes [49]; NCAM2, known as a liver progenitor cell marker and also expressed in acute and chronic damaged livers [50]; PROM1 and KIT, both having been reported as markers for liver progenitor cells [51]. Markers, such as SMAD4 and THY1 have also been shown to be expressed in liver progenitor cells [51][52][53][54].…”

Progenitor Cells in Liver Development, Regeneration and Repair

“…Studies demonstrate that Hepatic Progenitor Cells (HPCs), or oval cells, which are quiescent in the healthy liver, may be activated when the regenerative capacity of mature hepatocytes is severely impaired [37][38][39]. These activated postnatal HPCs express a variety of stem/progenitor markers such as EpCAM, OV6, Prominin1, CD49f, and A6 [15,[40][41][42][43].…”