{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T10:42:43Z","timestamp":1784976163646,"version":"3.55.0"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":167,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:p>\n                    Repair of cirrhotic livers occurs, in part, by repopulation with hepatocytes through the stem\/progenitor pathway. There remain many uncertainties regarding this pathway. Hepatocyte \u201cbuds\u201d occurring in broad septa are hypothesized to be the anatomic manifestation of this pathway. Our purpose was to define a morphologic sequence of bud maturation to allow a quantitative measure of the importance of the stem\/progenitor pathway in humans. Histologic sections from 37 liver resection specimens were stained with trichrome, epithelial cell adhesion molecule (EpCAM), K19, CD34, glutamine synthetase (GS), and Ki\u201067. Specimens were stratified by etiology (10 biliary, 22 nonbiliary, five controls) and stage. Buds were defined as clusters of hepatocytes within septa. Five levels of bud maturation (0\u20104) were defined by the progressive increase in hepatocyte progeny relative to cholangiocytes. Level 0 single\u2010cell buds are K19\n                    <jats:sup>+<\/jats:sup>\n                    \/GS\n                    <jats:sup>+<\/jats:sup>\n                    \/EpCAM\n                    <jats:sup>+<\/jats:sup>\n                    \/Heppar1\n                    <jats:sup>\u2212<\/jats:sup>\n                    . In level 1, the progeny are morphologically hepatocytes (K19\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/GS\n                    <jats:sup>+<\/jats:sup>\n                    \/EpCAM\n                    <jats:sup>+<\/jats:sup>\n                    \/Heppar1\n                    <jats:sup>+<\/jats:sup>\n                    ). In level 2\u20104 buds, hepatocytes increase and become progressively GS\n                    <jats:sup>\u2212<\/jats:sup>\n                    and EpCAM\n                    <jats:sup>\u2212<\/jats:sup>\n                    . Associated endothelium is CD34\n                    <jats:sup>+<\/jats:sup>\n                    in level 1\u20102 buds and becomes CD34\n                    <jats:sup>\u2212<\/jats:sup>\n                    near hepatic veins in level 3\u20104 buds. Progeny of the bud sequence may represent up to 70% of hepatocytes (immaturity index of 70%). In biliary disease, bud number is reduced in association with duct loss and cholestatic destruction of nascent buds.\n                    <jats:italic toggle=\"yes\">Conclusions<\/jats:italic>\n                    : The stem\/progenitor pathway, manifested anatomically by the bud sequence, is a major mechanism for repopulation of cirrhotic livers. The bud sequence reveals some critical features of hepatic morphogenesis, including that 1) the majority of distal cholangiocytes have stem\u2010like properties, and 2) availability of bile ducts and\/or venous drainage are limiting factors for regeneration. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2015;61:1696\u20131707)\n                  <\/jats:p>","DOI":"10.1002\/hep.27706","type":"journal-article","created":{"date-parts":[[2015,1,16]],"date-time":"2015-01-16T17:21:12Z","timestamp":1421428872000},"page":"1696-1707","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":108,"title":["Hepatocyte buds derived from progenitor cells repopulate regions of parenchymal extinction in human cirrhosis"],"prefix":"10.1097","volume":"61","author":[{"given":"Ashley E.","family":"Stueck","sequence":"first","affiliation":[{"name":"Department of Pathology,Queen Elizabeth II Health Sciences Centre,Halifax,NS,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian R.","family":"Wanless","sequence":"additional","affiliation":[{"name":"Department of Pathology,Queen Elizabeth II Health Sciences 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