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 http://www.selleckchem.com/products/AG-014699.html 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 selleck chemicals llc 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 上海皓元医药股份有限公司 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.