title: Cell turnover in the repopulated rat liver: distinct lineages for hepatocytes and the biliary epithelium.
abstract: The dynamics of cell renewal in the normal adult liver remains an unresolved issue. We investigate the possible contribution of a common biliary precursor cell pool to hepatocyte turnover in the chimeric long-term repopulated rat liver. The retrorsine (RS)-based model of massive liver repopulation was used. Animals not expressing the CD26 marker (CD26(-)) were injected with RS, followed by transplantation of 2 million syngeneic hepatocytes isolated from a normal CD26-expressing donor. Extensive (80-90%) replacement of resident parenchymal cells was observed at 1 year post-transplantation and persisted at 2 years, as expected. A panel of specific markers, including cytokeratin 7, OV6, EpCAM, claudin 7 and α-fetoprotein, was employed to locate the in situ putative progenitor and/or biliary epithelial cells in the stably repopulated liver. No overlap was observed between any of these markers and the CD26 tag identifying transplanted cells. Exposure to RS was not inhibitory to the putative progenitor and/or biliary epithelial cells, nor did we observe any evidence of cell fusion between these cells and the transplanted cell population. Given the long-term (>2 years) stability of the donor cell phenotype in this model of liver repopulation, the present findings suggest that hepatocyte turnover in the repopulated liver is fuelled by a cell lineage distinct from that of the biliary epithelium and relies largely on the differentiated parenchymal cell population. These results support the solid biological foundation of liver repopulation strategies based on the transplantation of isolated hepatocytes.
authors.affiliation: Department of Biomedical Sciences, Unit of Experimental Medicine, University of Cagliari School of Medicine, Via Porcell 4, 3rd Floor, Cagliari, 09124, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Marongiu
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Serra
authors.forename: Marcella
authors.initials: M
authors.lastname: Sini
authors.forename: Michela
authors.initials: M
authors.lastname: Marongiu
authors.forename: Antonella
authors.initials: A
authors.lastname: Contini
authors.forename: Ezio
authors.initials: E
authors.lastname: Laconi
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001652:Bile Ducts / Q000166:cytology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D019070:Cell Lineage; D057167:Claudins / Q000096:biosynthesis; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000378:metabolism*; D004848:Epithelium / Q000254:growth & development*; D022781:Hepatocytes / Q000637:transplantation*; D053552:Keratin-7 / Q000096:biosynthesis; D008099:Liver / Q000166:cytology*; D008115:Liver Regeneration / Q000187:drug effects; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D000509:alpha-Fetoproteins / Q000096:biosynthesis
chemical_list: D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D015815:Cell Adhesion Molecules; D057167:Claudins; C507360:Cldn7 protein, mouse; D000071858:Epithelial Cell Adhesion Molecule; D053552:Keratin-7; D011763:Pyrrolizidine Alkaloids; D000509:alpha-Fetoproteins; C115011:oval cell marker OV-6; D018819:Dipeptidyl Peptidase 4; C003300:retrorsine