title: Hypoxia-driven Hif2a coordinates mouse liver regeneration by coupling parenchymal growth to vascular expansion.
abstract: Interaction between sinusoidal endothelial cells and hepatocytes is a prerequisite for liver function. Upon tissue loss, both liver cell populations need to be regenerated. Repopulation occurs in a coordinated pattern, first through the regeneration of parenchyme (hepatocytes), which then produces vascular endothelial growth factor (VEGF) to enable the subsequent angiogenic phase. The signals that instruct hepatocytes to induce timely VEGF remain unidentified. Given that liver is highly vascularized, we reasoned that fluctuations in oxygenation after tissue loss may contribute to the coordination between hepatocyte and sinusoidal endothelial cell proliferation. To prevent drops in oxygen after hepatectomy, mice were pretreated with inositol trispyrophosphate (ITPP), an allosteric effector of hemoglobin causing increased O2release from heme under hypoxic conditions. ITPP treatment delayed liver weight gain after hepatectomy. Comparison with controls revealed the presence of a hypoxic period around the peak of hepatocyte mitosis. Inhibition of hypoxia led to deficient hepatocyte mitosis, suppressed the regenerative Vegf wave, and abrogated the subsequent reconstruction of the sinusoidal network. These ITPP effects were ongoing with the reduction in hepatocellular hypoxia inducible factor 2a (Hif2a). In contrast, Hif1a was unaffected by ITPP. Hif2a knockdown phenocopied all effects of ITPP, including the mitotic deficiencies, Vegf suppression, and angiogenic failure.
  
  
  
  Oxygen is a key regulator of liver regeneration. Hypoxia-inherent to the expansion of parenchyme-activates Hif2a to couple hepatocyte mitosis with the angiogenic phase. Hif2a acts as a safeguard to initiate sinusoidal reconstruction only upon successful hepatocyte mitosis, thereby enforcing a timely order onto cell type-specific regeneration patterns. These findings portray the hypoxia-driven Hif2a-Vegf axis as a prime node in coordinating sinusoidal endothelial cell-hepatocyte crosstalk during liver regeneration. (Hepatology 2016;64:2198-2209).
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kron
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Linecker
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Perparim
authors.initials: P
authors.lastname: Limani
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schlegel
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Patryk
authors.initials: P
authors.lastname: Kambakamba
authors.affiliation: Institut de Science et d'Ingénierie Supramoléculaires, Université de Strasbourg, Strasbourg, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Lehn
authors.affiliation: Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA.
authors.forename: Claude
authors.initials: C
authors.lastname: Nicolau
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology; D008099:Liver / Q000098:blood supply; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D000072356:Parenchymal Tissue / Q000254:growth & development*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1