{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T05:02:22Z","timestamp":1771304542612,"version":"3.50.1"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2017,3,27]],"date-time":"2017-03-27T00:00:00Z","timestamp":1490572800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:p>The liver is well known to possess high regenerative capacity in response to partial resection or tissue injury. However, liver regeneration is often impaired in the case of advanced liver fibrosis\/cirrhosis when mature hepatocytes can hardly self\u2010proliferate. Hepatic progenitor cells have been implicated as a source of hepatocytes in regeneration of the fibrotic liver. Although alpha\u2010fetoprotein (AFP) is known as a clinical marker of progenitor cell induction in injured\/fibrotic adult liver, the origin and features of such AFP\u2010producing cells are not fully understood. Here, we demonstrate a unique and distinct AFP\u2010expressing cell population that is induced by the Jagged1\/Notch2 signal in murine fibrotic liver. Following repeated carbon tetrachloride injections, a significant number of AFP\u2010positive cells with high proliferative ability were observed along the fibrous septa depending on the extent of liver fibrosis. These AFP\u2010positive cells exhibited features of immature hepatocytes that were stained positively for hepatocyte\u2010lineage markers, such as albumin and hepatocyte nuclear factor 4 alpha, and a stem\/progenitor cell marker Sox9. A combination of immunohistological examination of fibrotic liver tissues and coculture experiments with primary hepatocytes and hepatic stellate cells indicated that increased Jagged1 expression in activated hepatic stellate cells stimulated Notch2 signaling and up\u2010regulated AFP expression in adjacent hepatocytes. The mobilization and proliferation of AFP\u2010positive cells in fibrotic liver were further enhanced after partial hepatectomy, which was significantly suppressed in Jagged1\u2010conditional knockout mice. Finally, forced expression of the intracellular domain of Notch2 in normal liver induced a small number of AFP\u2010expressing hepatocytes <jats:italic toggle=\"yes\">in vivo. Conclusion<\/jats:italic>: Insight is provided into a novel pathophysiological role of Jagged1\/Notch2 signaling in the induction of AFP\u2010positive cells in fibrotic liver through the interaction between hepatocytes and activated hepatic stellate cells. (<jats:italic toggle=\"yes\">Hepatology Communications<\/jats:italic> 2017;1:215\u2010229)<\/jats:p>","DOI":"10.1002\/hep4.1026","type":"journal-article","created":{"date-parts":[[2017,3,27]],"date-time":"2017-03-27T11:47:23Z","timestamp":1490615243000},"page":"215-229","source":"Crossref","is-referenced-by-count":35,"title":["Identification of a novel alpha\u2010fetoprotein\u2010expressing cell population induced by the Jagged1\/Notch2 signal in murine fibrotic liver"],"prefix":"10.1097","volume":"1","author":[{"given":"Yasuhiro","family":"Nakano","sequence":"first","affiliation":[{"name":"Center for Matrix Biology and Medicine,Graduate School of Medicine, Tokai University,Isehara,Japan"},{"name":"Department of Regenerative Medicine, Tokai University School of Medicine,Isehara,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sachie","family":"Nakao","sequence":"additional","affiliation":[{"name":"Center for Matrix Biology and Medicine,Graduate School of Medicine, Tokai University,Isehara,Japan"},{"name":"Department of Regenerative Medicine, Tokai University School of Medicine,Isehara,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideaki","family":"Sumiyoshi","sequence":"additional","affiliation":[{"name":"Center for Matrix Biology and Medicine,Graduate School of Medicine, Tokai University,Isehara,Japan"},{"name":"Department of Regenerative Medicine, Tokai University School of Medicine,Isehara,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichiro","family":"Mikami","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Tokai University School of Medicine,Isehara,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuri","family":"Tanno","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Tokai University School of Medicine,Isehara,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minako","family":"Sueoka","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Tokai University School of Medicine,Isehara,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daigo","family":"Kasahara","sequence":"additional","affiliation":[{"name":"Center for Matrix Biology and Medicine,Graduate School of Medicine, Tokai University,Isehara,Japan"},{"name":"Department of Mechanical Engineering,Tokai University School of Engineering,Hiratsuka,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering,Tokai University School of Engineering,Hiratsuka,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadashi","family":"Moro","sequence":"additional","affiliation":[{"name":"Center for Matrix Biology and 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