title: Epiregulin promotes the emergence and proliferation of adult liver progenitor cells.
abstract: We have previously reported that epiregulin is a growth factor that seems to act on liver progenitor cells (LPCs) during liver regeneration. However, the relationship between epiregulin and LPCs has remained unclear. The aim of the present study was to clarify the role of epiregulin during liver regeneration. The serum levels of epiregulin in patients with acute liver failure were examined. A liver injury model was developed using mice fed a diet containing 0.1% 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) to induce LPCs. We then evaluated the expression of epiregulin and LPCs in these mice. The proliferation of epithelial cell adhesion molecule + LPCs cultured with epiregulin was examined in vitro, and finally epiregulin was overexpressed in mouse liver. In patients with acute liver failure, serum epiregulin levels were elevated significantly. In DDC mice, LPCs emerged around the portal area. Epiregulin was also detected around the portal area during the course of DDC-induced liver injury and was partially coexpressed with Thy1. Serum epiregulin levels in DDC mice were also significantly elevated. Recombinant epiregulin augmented the proliferative capacity of the LPCs in a dose-dependent manner. In mice showing overexpression of epiregulin, the expression of PCNA on hepatocytes was increased significantly. Finally, LPCs emerged around the portal area after epiregulin gene delivery. We concluded that epiregulin promotes the proliferation of LPCs and DNA synthesis by hepatocytes and is upregulated in the serum of patients with liver injury. Furthermore, induction of epiregulin leads to the appearance of LPCs. Epiregulin would be a useful biomarker of liver regeneration.
authors.affiliation: Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan; CREST, Yamagata University Faculty of Medicine, Yamagata, Japan to.kyoko@med.id.yamagata-u.ac.jp.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan;
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Haga
authors.affiliation: Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan; CREST, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan;
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Katsumi
authors.affiliation: Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan; CREST, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Sato
authors.affiliation: Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan;
authors.forename: Kazuo
authors.initials: K
authors.lastname: Okumoto
authors.affiliation: Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan;
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nishise
authors.affiliation: Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan; CREST, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan;
authors.forename: Takafumi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan; CREST, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ueno
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004261:DNA Replication; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D066260:Epiregulin; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology; D018800:Thy-1 Antigens / Q000378:metabolism; D013997:Time Factors
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C587880:EREG protein, human; D066260:Epiregulin; D000071858:Epithelial Cell Adhesion Molecule; C587881:Ereg protein, mouse; D011994:Recombinant Proteins; D018800:Thy-1 Antigens; D004815:Epidermal Growth Factor
keywords: Thy1; epiregulin; epithelial cell adhesion molecule; liver injury; liver regeneration; progenitor cells