title: Ablation of Foxl1-Cre-labeled hepatic progenitor cells and their descendants impairs recovery of mice from liver injury.
abstract: OBJECTIVE
  Foxl1(+) hepatic progenitor cells (HPCs) differentiate into cholangiocytes and hepatocytes after liver injury. We investigated the requirement for Foxl1(+) HPCs in recovery from liver injury in mice.
  
  
  METHODS
  We developed mice in which we could trace and delete Foxl1-expressing HPCs and their descendants (Foxl1-Cre;Rosa(YFP/iDTR)-inducible diphtheria toxin receptor [iDTR] mice). Foxl1-Cre-negative mice were used as controls. Liver damage was induced in male mice by placing them on choline-deficient, ethionine-supplemented (CDE) diets for 15 days; mice then were placed on normal diets and allowed to recover. Liver damage was induced in female mice by placing them on 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diets, followed by a recovery period. Some mice were given injections of diphtheria toxin during the recovery phase to delete Foxl1-Cre-marked HPCs and their descendants. Livers were collected from all mice and analyzed by immunofluorescence, quantitative reverse-transcription polymerase chain reaction, flow cytometry, and histologic analyses.
  
  
  RESULTS
  Foxl1-Cre-marked HPCs were required for the development of cholangiocytes and hepatocytes in livers after CDE diet-induced injury. A smaller percentage of yellow fluorescent protein-positive (YFP(+)) hepatocytes contained markers of oxidative stress, DNA damage, or cell death than YFP-negative hepatocytes, indicating that YFP(+) hepatocytes are newly formed cells. Injection of diphtheria toxin deleted YFP(+) cells from Foxl1-Cre;Rosa(YFP/iDTR) mice and prevented the resolution of hepatic steatosis. In mice recovering from DDC diet-induced injury, most cholangiocytes arose from Foxl1-Cre-marked HPCs. Deletion of YFP(+) cells did not alter levels of markers of liver injury or liver function.
  
  
  CONCLUSIONS
  Based on studies of Foxl1-Cre;Rosa(YFP/iDTR) mice, Foxl1(+) HPCs and/or their descendants are required for the development of cholangiocytes and hepatocytes in liver after CDE diet-induced injury.
authors.affiliation: Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Soona
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Naman
authors.initials: N
authors.lastname: Upadhyay
authors.affiliation: Departments of Cancer Biology and Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Greenbaum
authors.affiliation: Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Electronic address: kaestner@mail.med.upenn.edu.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D019070:Cell Lineage; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002796:Choline Deficiency / Q000150:complications; D004249:DNA Damage; D004195:Disease Models, Animal; D005001:Ethionine; D005260:Female; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000235:genetics*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D018384:Oxidative Stress; D011725:Pyridines; D022661:RNA, Untranslated / Q000235:genetics; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D001426:Bacterial Proteins; D051858:Forkhead Transcription Factors; C099993:Foxl1 protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D066257:Heparin-binding EGF-like Growth Factor; D008164:Luminescent Proteins; D011725:Pyridines; D022661:RNA, Untranslated; C054562:yellow fluorescent protein, Bacteria; C045073:Cre recombinase; D019426:Integrases; D005001:Ethionine
keywords: HPCs; Mouse Model; Nonalcoholic Fatty Liver Disease; Oval Cells