Transit-amplifying ductular (oval) cells and their hepatocytic progeny are characterized by a novel and distinctive expression of delta-like protein/preadipocyte factor 1/fetal antigen 1.
Hepatic regeneration from toxic or surgical injury to the adult mammalian liver, endorses different cellular responses within the hepatic lineage. The molecular mechanisms determining commitment of a cell population at a specific lineage level to participate in liver repair as well as the fate of its progeny in the hostile environment created by the injury are not well defined. Based on the role of the Notch/Delta/Jagged system in cell fate specification and recent reports linking Notch signaling with normal bile duct formation in mouse and human liver, we examined the expression of Notch1, Notch2, Notch3, Delta1, Delta3, Jagged1, and Jagged2, and delta-like protein/preadipocyte factor 1/fetal antigen 1 (dlk) in four well-defined experimental rat models of liver injury and regeneration. Although Delta3 and Jagged2 were undetectable by reverse transcriptase-polymerase chain reaction and Northern blot, we observed the most significant up-regulation of all other transcripts in the 2-acetylaminofluorene-70% hepatectomy (AAF/PHx) model, in which liver mass is restored by proliferation and differentiation of transit-amplifying ductular (oval) cells. The most profound change was observed for dlk. Accordingly, immunohistochemical analyses in the AAF/PHx model showed a specific expression of dlk in atypical ductular structures composed of oval cells. Delta-like protein was not observed in proliferating hepatocytes or bile duct cells after partial hepatectomy or ligation of the common bile duct whereas clusters of dlk immunoreactive oval cells were found in both the retrorsine and the AAF/PHx models. Finally, we used dlk to isolate alpha-fetoprotein-positive cells from fetal and adult regenerating rat liver by a novel antibody panning technique.
Jensen
Charlotte Harken
CH
Department of Immunology and Microbiology, Danish Stem Cell Research Center, University of Southern Denmark, Odense, Denmark.
Jauho
Eva Irene
EI
Santoni-Rugiu
Eric
E
Holmskov
Uffe
U
Teisner
Børge
B
Tygstrup
Niels
N
Bisgaard
Hanne Cathrine
HC
D000818:Animals; D015152:Blotting, Northern; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000096:biosynthesis; D006023:Glycoproteins / Q000096:biosynthesis; D006500:Hepatic Duct, Common / Q000166:cytology* / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008099:Liver / Q000166:cytology / Q000293:injuries / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D014176:Protein Biosynthesis; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C512941:DLK1 protein, human; C512925:Dlk1 protein, mouse; C512923:Dlk1 protein, rat; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C490504:JAG2 protein, human; C000606274:Jag1 protein, mouse; C000606275:Jag1 protein, rat; C490503:Jag2 protein, mouse; C490502:Jag2 protein, rat; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C497763:Notch1 protein, rat; C497766:Notch2 protein, rat; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; C064045:delta protein