title: CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice.
abstract: The role of stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptor CXC chemokine receptor-4 (CXCR4) in ischemic liver injury and recovery has not been studied. Some reports suggest that this chemokine may aid in liver regeneration, but others suggest that it may be profibrotic through its activation of hepatic stellate cells. In this study we sought to elucidate the role of SDF-1 and its receptor CXCR4 during liver injury, recovery, and regeneration after ischemia-reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. CXCR4 was expressed constitutively in the liver, and hepatic levels of SDF-1 peaked 8 h after reperfusion but remained significantly increased for 96 h. Treatment of mice with the CXCR4 antagonist AMD3100 or agonist SDF-1 had no effect on acute liver injury assessed 8 h after I/R. However, treatment with AMD3100 increased hepatocyte proliferation after 72 and 96 h of reperfusion and reduced the amount of liver necrosis. In contrast, treatment with SDF-1 significantly decreased hepatocyte proliferation. These effects appeared to be dependent on the presence of liver injury, as AMD3100 and SDF-1 had no effect on hepatocyte proliferation or liver mass in mice undergoing 70% partial hepatectomy. The data suggest that signaling through CXCR4 is detrimental to liver recovery and regeneration after I/R and that clinical therapy with a CXCR4 antagonist may improve hepatic recovery following acute liver injury.
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Wilson
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Kuethe
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Quillin
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nojima
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schuster
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: John
authors.initials: J
authors.lastname: Blanchard
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Caldwell
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio alex.lentsch@uc.edu.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001596:Benzylamines; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism* / Q000494:pharmacology; D000080027:Cyclams; D004195:Disease Models, Animal; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000637:transplantation; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; C088327:plerixafor
keywords: CXCR4; chemokines; liver regeneration; progenitor cells; stromal cell-derived factor-1