title: Cord blood CD133 cells define an OV6-positive population that can be differentiated in vitro into engraftable bipotent hepatic progenitors.
abstract: Cell therapy represents the most promising alternative strategy for end-stage liver diseases and hepatic progenitors are the best candidates. We have identified a reservoir of immature hepatic precursors within human cord blood, which can derive engraftable bipotent progenitors. We isolated a stem cell subset CD133+/CD34+/OV6(low) expressing a surface-marker profile consistent with that of fetal liver cells. Upon induction of hepatic commitment by a medium containing cytokines and factors involved in vivo oval-cell activation, a heterogeneous cell population displaying characteristics of functional oval-cell-like bipotent hepatic progenitors was obtained. The cells expressed markers of hepatocytes and cholangiocytes and were highly enriched in OV6, c-Met, c-Kit, and Thy-1. They also displayed liver functional activity as glycogen storage, urea production, albumin secretion, and inducible CyP2B6 activity. When injected into liver-damaged severe-combined immunodeficient mice, induced bipotent hepatic progenitors appropriately engrafted livers of recipient animals, where they formed clusters of human-derived cells expressing human leucocyte antigen-class I, Hep-Par1, and OV6 antigens. Human-specific albumin, alpha-fetoprotein, and cytokeratin 19 were also expressed. In transplanted animals, AST serum levels showed a significative reduction with regard to controls. This human model for in vitro progenitor-cell activation may provide a powerful tool for elucidating the pathways and synergies that regulate this complex process and can represent a valuable source, exploitable for liver cell-based therapies and regenerative medicine.
authors.affiliation: Institute of Translational Pharmacology, Department of Medicine, National Research Council (CNR), Rome, Italy. annalisa.crema@ift.cnr.it
authors.forename: Annalisa
authors.initials: A
authors.lastname: Crema
authors.forename: Mario
authors.initials: M
authors.lastname: Ledda
authors.forename: Flavia
authors.initials: F
authors.lastname: De Carlo
authors.forename: Daniela
authors.initials: D
authors.lastname: Fioretti
authors.forename: Monica
authors.initials: M
authors.lastname: Rinaldi
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Marchese
authors.forename: Massimo
authors.initials: M
authors.lastname: Sanchez
authors.forename: Massimo
authors.initials: M
authors.lastname: Giuliani
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arena
authors.forename: Antoine
authors.initials: A
authors.lastname: Durrbach
authors.forename: Ercole
authors.initials: E
authors.lastname: Brunetti
authors.forename: Cristina
authors.initials: C
authors.lastname: Haas
authors.forename: Antonio
authors.initials: A
authors.lastname: Ponzetto
authors.forename: Antonella
authors.initials: A
authors.lastname: Lisi
authors.forename: Guido
authors.initials: G
authors.lastname: Carloni
mesh_terms: D000071916:AC133 Antigen; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D018952:Antigens, CD34 / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D048430:Cell Shape; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology*; D015870:Gene Expression; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D053539:Keratin-19 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000628:therapy; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D015415:Biomarkers; D006023:Glycoproteins; D053539:Keratin-19; D008077:Lipoproteins, LDL; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D000509:alpha-Fetoproteins; C115011:oval cell marker OV-6; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase