title: Hepatic progenitor cells of biliary origin with liver repopulation capacity.
abstract: Hepatocytes and cholangiocytes self-renew following liver injury. Following severe injury hepatocytes are increasingly senescent, but whether hepatic progenitor cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where the E3 ubiquitin ligase Mdm2 is inducibly deleted in more than 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution. HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease.
authors.affiliation: MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Lu
authors.affiliation: MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Bird
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, EH4 2XU.
authors.forename: Luke
authors.initials: L
authors.lastname: Boulter
authors.affiliation: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Tsuchiya
authors.affiliation: The CRUK Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow, G61 1BD.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Cole
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, CF24 4HQ.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hay
authors.affiliation: MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU.
authors.forename: Rachel V
authors.initials: RV
authors.lastname: Guest
authors.affiliation: MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU.
authors.forename: Davina
authors.initials: D
authors.lastname: Wojtacha
authors.affiliation: MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU.
authors.forename: Tak Yung
authors.initials: TY
authors.lastname: Man
authors.affiliation: MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU.
authors.forename: Alison
authors.initials: A
authors.lastname: Mackinnon
authors.affiliation: The CRUK Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow, G61 1BD.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, EH4 2XU.
authors.forename: Timothy
authors.initials: T
authors.lastname: Kendall
authors.affiliation: MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Williams
authors.affiliation: The CRUK Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow, G61 1BD.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jamieson
authors.affiliation: MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU.
authors.forename: Alex
authors.initials: A
authors.lastname: Raven
authors.affiliation: MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU.
authors.forename: David C
authors.initials: DC
authors.lastname: Hay
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, CF24 4HQ.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
authors.affiliation: The CRUK Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow, G61 1BD.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
mesh_terms: D000818:Animals; D017209:Apoptosis; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D005260:Female; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000172:deficiency / Q000235:genetics; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D015415:Biomarkers; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2