Ablation of Foxl1-Cre-labeled hepatic progenitor cells and their descendants impairs recovery of mice from liver injury

Gastroenterology. 2015 Jan;148(1):192-202.e3. doi: 10.1053/j.gastro.2014.09.039. Epub 2014 Oct 5.

Abstract

Background & aims: 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.

Keywords: HPCs; Mouse Model; Nonalcoholic Fatty Liver Disease; Oval Cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Bile Ducts, Intrahepatic / metabolism
  • Bile Ducts, Intrahepatic / pathology
  • Cell Death
  • Cell Lineage*
  • Cell Proliferation*
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology
  • Choline Deficiency / complications
  • DNA Damage
  • Disease Models, Animal
  • Ethionine
  • Female
  • Forkhead Transcription Factors / deficiency*
  • Forkhead Transcription Factors / genetics
  • Heparin-binding EGF-like Growth Factor / genetics
  • Heparin-binding EGF-like Growth Factor / metabolism
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Integrases / genetics*
  • Liver / metabolism*
  • Liver / pathology
  • Liver Regeneration*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Mice, Knockout
  • Oxidative Stress
  • Pyridines
  • RNA, Untranslated / genetics
  • Signal Transduction
  • Stem Cells / metabolism*
  • Stem Cells / pathology
  • Time Factors

Substances

  • 3,5-diethoxycarbonyl-1,4-dihydrocollidine
  • Bacterial Proteins
  • Forkhead Transcription Factors
  • Foxl1 protein, mouse
  • Gt(ROSA)26Sor non-coding RNA, mouse
  • Heparin-binding EGF-like Growth Factor
  • Luminescent Proteins
  • Pyridines
  • RNA, Untranslated
  • yellow fluorescent protein, Bacteria
  • Cre recombinase
  • Integrases
  • Ethionine