Of particular importance have been studies showing that EpCAM is a marker of the hepatobiliary stem cell niche and that when such cells develop into hepatocytes in culture, the new hepatocytes as well as the cells with intermediate features between stem/progenitor cells and hepatocytes also display membranous EpCAM.2, 16 These findings led us to hypothesize that EpCAM(+) hepatocytes are derived relatively recently from the stem cell niche Pexidartinib rather

than from other, preexisting hepatocytes. The goal of the present study was to investigate this possibility within intact tissue specimens from livers of patients with hepatitis B and C through several means. The first is by determining whether EpCAM(+) hepatocytes develop only in the context of ductular reactions, stage by stage, and exploring the topological relationships GSK1120212 of

these cells (Fig. 1 and Table 3). Four important points support our primary hypothesis: (1) EpCAM(+) hepatocytes, like ductular reactions, increase in frequency and extent with increasing stage of disease; (2) although ductular reactions sometimes do not have associated EpCAM(+) hepatocytes, EpCAM(+) hepatocytes, when present, are always associated with ductular reactions; (3) EpCAM(+) hepatocytes always appear as aggregates surrounding a core of ductular reaction cells; and (4) cells of intermediate morphology between the smallest progenitor cells of the ductular reaction and mature appearing, EpCAM(+) hepatocytes are always also EpCAM(+). Thus, morphologically, topographically, and immunophenotypically, EpCAM(+) hepatocytes click here appear to derive from cells of the ductular reaction. Such data, although compelling, are incomplete. We thus hypothesized that if EpCAM(+) hepatocytes were stem cell–derived, they would have telomere lengths that were longer than those of the EpCAM(−) hepatocytes. This hypothesis is based on prior

data indicating that ductular reactions have increased telomerase activation22-25 and that senescent hepatocytes, after years of increased cell turnover, would have shortened telomeres.26-29 We would also expect that EpCAM(−) hepatocytes in cirrhosis would have telomeres that would be shorter than those in EpCAM(+) hepatocytes, and that telomere length of EpCAM(+) hepatocytes would be shorter than that in ductular reactions. These predictions were confirmed in a statistically meaningful way for hepatocytes in CHB cirrhosis. We also sought to explore issues of proliferation and senescence as previous studies had done,13-15, 20 but discriminating between hepatocytes that were EpCAM(+) and those that were EpCAM(−). However, there was no significant difference of PCNA and p21 labeling indices between EpCAM(+) hepatocytes and EpCAM(−) hepatocytes.