title: Monocyte-endothelial cell interactions in the regulation of vascular sprouting and liver regeneration in mouse.
abstract: OBJECTIVE
  Regeneration of the hepatic mass is crucial to liver repair. Proliferation of hepatic parenchyma is intimately dependent on angiogenesis and resident macrophage-derived cytokines. However the role of circulating monocyte interactions in vascular and hepatic regeneration is not well-defined. We investigated the role of these interactions in regeneration in the presence and absence of intact monocyte adhesion.
  
  
  METHODS
  Partial hepatectomy was performed in wild-type mice and those lacking the monocyte adhesion molecule CD11b. Vascular architecture, angiogenesis and macrophage location were analyzed in the whole livers using simultaneous angiography and macrophage staining with fluorescent multiphoton microscopy. Monocyte adhesion molecule expression and sprouting-related pathways were evaluated.
  
  
  RESULTS
  Resident macrophages (Kupffer cells) did not migrate to interact with vessels whereas infiltrating monocytes were found adjacent to sprouting points. Infiltrated monocytes colocalized with Wnt5a, angiopoietin 1 and Notch-1 in contact points and commensurate with phosphorylation and disruption of VE-cadherin. Mice deficient in CD11b showed a severe reduction in angiogenesis, liver mass regeneration and survival following partial hepatectomy, and developed unstable and leaky vessels that eventually produced an aberrant hepatic vascular network and Kupffer cell distribution.
  
  
  CONCLUSIONS
  Direct vascular interactions of infiltrating monocytes are required for an ordered vascular growth and liver regeneration. These outcomes provide insight into hepatic repair and new strategies for hepatic regeneration.
authors.affiliation: Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: pedroml@mit.edu.
authors.forename: Pedro
authors.initials: P
authors.lastname: Melgar-Lesmes
authors.affiliation: Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Elazer R
authors.initials: ER
authors.lastname: Edelman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D002450:Cell Communication; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology*; D005786:Gene Expression Regulation; D006498:Hepatectomy / Q000009:adverse effects; D021621:Imaging, Three-Dimensional; D007113:Immunity, Innate; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008115:Liver Regeneration / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology*; D018919:Neovascularization, Physiologic / Q000276:immunology*; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015815:Cell Adhesion Molecules; D012313:RNA
keywords: Angiogenesis; Hepatic repair; Immunology; Innate immune system