title: Generation and characterization of rat liver stem cell lines and their engraftment in a rat model of liver failure.
abstract: The rat is an important model for liver regeneration. However, there is no in vitro culture system that can capture the massive proliferation that can be observed after partial hepatectomy in rats. We here describe the generation of rat liver stem cell lines. Rat liver stem cells, which grow as cystic organoids, were characterized by high expression of the stem cell marker Lgr5, by the expression of liver progenitor and duct markers, and by low expression of hepatocyte markers, oval cell markers, and stellate cell markers. Prolonged cultures of rat liver organoids depended on high levels of WNT-signalling and the inhibition of BMP-signaling. Upon transplantation of clonal lines to a Fah(-/-) Il2rg(-/-) rat model of liver failure, the rat liver stem cells engrafted into the host liver where they differentiated into areas with FAH and Albumin positive hepatocytes. Rat liver stem cell lines hold potential as consistent reliable cell sources for pharmacological, toxicological or metabolic studies. In addition, rat liver stem cell lines may contribute to the development of regenerative medicine in liver disease. To our knowledge, the here described liver stem cell lines represent the first organoid culture system in the rat.
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands.|University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands.
authors.forename: Ewart W
authors.initials: EW
authors.lastname: Kuijk
authors.affiliation: Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Shauna
authors.initials: S
authors.lastname: Rasmussen
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands.|University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands.
authors.forename: Francis
authors.initials: F
authors.lastname: Blokzijl
authors.affiliation: Wellcome Trust/MRC Stem Cell Institute, Department of Physiology, Development and Neuroscience, University of Cambridge, Tennis Court Rd, Cambridge CB2 1QN, UK.|Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Rd, Cambridge CB2 1QN, UK.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Huch
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands.
authors.forename: Helmuth
authors.initials: H
authors.lastname: Gehart
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: Toonen
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Begthel
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.|Human and Molecular Genetics Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, 53226, WI, USA.
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands.|University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism* / Q000637:transplantation*; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000166:cytology; D017093:Liver Failure / Q000473:pathology / Q000628:therapy*; D008115:Liver Regeneration / Q000502:physiology*; D016031:Liver Transplantation; D051381:Rats; D055647:Rats, Transgenic; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D060509:Wnt3A Protein / Q000494:pharmacology; D000099176:Noggin Protein
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D006867:Hydrolases; D053631:Interleukin Receptor Common gamma Subunit; D060509:Wnt3A Protein; D000099176:Noggin Protein; C020156:fumarylacetoacetase