title: Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate.
abstract: OBJECTIVE
  Exosomes are small membrane vesicles involved in intercellular communication. Hepatocytes are known to release exosomes, but little is known about their biological function. We sought to determine if exosomes derived from hepatocytes contribute to liver repair and regeneration after injury.
  
  
  METHODS
  Exosomes derived from primary murine hepatocytes were isolated and characterized biochemically and biophysically. Using cultures of primary hepatocytes, we tested whether hepatocyte exosomes induced proliferation of hepatocytes in vitro. Using models of ischemia/reperfusion injury and partial hepatectomy, we evaluated whether hepatocyte exosomes promote hepatocyte proliferation and liver regeneration in vivo.
  
  
  RESULTS
  Hepatocyte exosomes, but not exosomes from other liver cell types, induce dose-dependent hepatocyte proliferation in vitro and in vivo. Mechanistically, hepatocyte exosomes directly fuse with target hepatocytes and transfer neutral ceramidase and sphingosine kinase 2 (SK2) causing increased synthesis of sphingosine-1-phosphate (S1P) within target hepatocytes. Ablation of exosomal SK prevents the proliferative effect of exosomes. After ischemia/reperfusion injury, the number of circulating exosomes with proliferative effects increases.
  
  
  CONCLUSIONS
  Our data shows that hepatocyte-derived exosomes deliver the synthetic machinery to form S1P in target hepatocytes resulting in cell proliferation and liver regeneration after ischemia/reperfusion injury or partial hepatectomy. These findings represent a potentially novel new contributing mechanism of liver regeneration and have important implications for new therapeutic approaches to acute and chronic liver disease.
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nojima
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Schuster
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA; Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA. Electronic address: alex.lentsch@uc.edu.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D055354:Exosomes / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology; D008115:Liver Regeneration; D008246:Lysophospholipids / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D000099157:Sphingosine Kinase
chemical_list: D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; C060506:sphingosine 1-phosphate; C000603447:sphingosine kinase 2, mouse; D000099157:Sphingosine Kinase
keywords: Ischemia/reperfusion; Liver injury; Sphingolipids; Sphingosine kinase; Transplantation