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- 저자 : ( Neil D Theise ) (검색결과 6 건)
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Liver Stem Cells: The Niche, Plasticity, Quiescence and Self-renewal
( Neil Theise ) 대한간학회 2007 추계 학술대회 Vol.13 No.-
Four putative intrahepatic stem cells have been hypothesized: 1. Intrabiliary stem cells in the intralobular bile ducts, defined initially by electron microscopic examination, immunohistochemical markers (e.g. c-kit), and three dimensional structural studies of human ductular reactions in cirrhosis; 2. Intrabiliary stem cells in the most proximal branches of the biliary tree, i.e. the canals of Hering and ductules, also defined by careful temporal studies of oval cell proliferations in rodents and by three dimensional structural studies in regenerating liver after severe acute toxic injury in humans; 3. Peribiliary monocytes, which have been termed "null cells" in rodent models of periportal injury. While they have a morphologic appearance identical to oval cells identified in standard, non-periportal experimental models of injury, they are lacking in the usual hepatobiliary markers (e.g. cytokeratins 7 and 19, alpha- fetoprotein, OV6, A6). 4. Periportal hepatocytes in the so called "streaming liver" model. This hypothesis was founded on the concept that the liver acinus is similar to other glandular organs and that there is movement from the periportal, limiting plate of hepatocytes, toward the central vein of the corresponding acinus, as the liver ages, much in the way that stem cells in the crypts of the intestinal tract give rise to cells that move up the crypt (and villous in the small intestine) to age and die at the top of the structure. However, this hypothesis was largely discredited many years ago by BRDU incorporation studies failing to demonstrate preferential cell division at the limiting plate. The varying evidence for the existence of these populations and a variety of hypotheses regarding their possible roles in liver maintenance and regeneration is difficult to evaluate definitively. New approaches have been developed in recent years, however. The current state of the art in vivo assay for stem cells, the "label retaining cell" assay, identifies not only stem cell populations but also their normal microanatomic location, the stem cell "niche." This assay exploits defined stem cell behaviors, namely rare division into another, rarely dividing daughter stem cell and a second daughter cell that begins a cascade of rapid, "transit amplifying" divisions. By supplying label as a pulse at the time of stem cell division, the quiescent daughter stem cell will take up label and retain it, while the transit amplifying cells will dilute the label to the point of undetectability. Thus, the label retaining cell will identify resident stem cells in the liver and indicate the location of the stem cell niche(s). Preliminary label retaining cell studies for the liver will be reported with presentation of data regarding possible stem cell niches for the liver. Some newly defined anatomic details of some of these niches, which may have experimental and clinical relevance in the future will also be discussed.
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Yoon, So‐,Mi,Gerasimidou, Domniki,Kuwahara, Reiichiro,Hytiroglou, Prodromos,Yoo, Jeong Eun,Park, Young Nyun,Theise, Neil D. Wiley Subscription Services, Inc., A Wiley Company 2011 Hepatology Vol.53 No.3
<P><B>Abstract</B></P><P>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(+) 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(+) 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(+) hepatocytes in cirrhosis were higher than EpCAM(−) hepatocytes (<I>P</I> < 0.046), and relatively shorter than those in the corresponding ductular reaction hepatobiliary cells (<I>P</I> = 0.057). <I>Conclusion:</I> These morphologic, topographic, immunophenotypic, and molecular data support the concept that EpCAM(+) 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. (H<SMALL>EPATOLOGY</SMALL> 2011)</P>
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Park, Young Nyun,Kojiro, Masamichi,Di Tommaso, Luca,Dhillon, Amar P.,Kondo, Fukuo,Nakano, Masayuki,Sakamoto, Michiie,Theise, Neil D.,Roncalli, Massimo John Wiley & Sons 2007 Cancer Vol.109 No.5
<B>BACKGROUND.</B><P>Stromal invasion is 1 of the main features used to distinguish high-grade dysplastic nodules (DNs) from well-differentiated hepatocellular carcinomas (HCCs). The authors hypothesized that ductular reaction (DR) takes place around noninvasive hepatocellular nodules but not within the stroma contiguous to invasive HCC.</P><B>METHODS.</B><P>DR/cytokeratin 7 (CK7)-positive patterns were evaluated in 105 resected small hepatic nodules according to the level of invasion. The nodules were classified histologically prior to immunostaining as noninvasive (large regenerative nodules, low-grade DNs, and high-grade DNs), minimally invasive (early HCCs with a vaguely nodular type), and overtly invasive (typical HCCs with a distinctly nodular type) in a review by expert pathologists, the current gold standard. Intranodular DR (inner DR) and DR around the nodule periphery (outer DR) were assessed separately on a semiquantitative scale from 0 to 4+.</P><B>RESULTS.</B><P>DR was 3 or 4+ in the majority of noninvasive nodules (inner DR, 81%; outer DR, 91%), whereas DR was 0 or 1+ in overtly invasive HCCs (inner DR, 96%; outer DR, 81%). Minimally invasive HCCs showed an intermediate DR pattern (2 or 3+ inner DR, 75%; 2+ outer DR, 67%). DR characteristically was absent at the stromal-invasive, leading edge of tumor cells in both minimally invasive HCCs (focal loss of DR/CK7) and overtly invasive HCCs (diffuse loss of DR/CK7). The DR patterns in 41 needle-biopsy samples were similar to the patterns observed in resected nodules.</P><B>CONCLUSIONS.</B><P>DR/CK7 immunostaining may help to identify small foci of invasion and to distinguish noninvasive, high-grade DNs from both minimally invasive and overtly invasive HCCs. Cancer 2007 © 2007 American Cancer Society.</P>
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