title: Tumor necrosis factor-alpha and endothelial cells modulate Notch signaling in the bone marrow microenvironment during inflammation.
abstract: OBJECTIVE
  Homeostasis of the hematopoietic compartment is challenged and maintained during conditions of stress by mechanisms that are poorly defined. To understand how the bone marrow (BM) microenvironment influences hematopoiesis, we explored the role of Notch signaling and BM endothelial cells in providing microenvironmental cues to hematopoietic cells in the presence of inflammatory stimuli.
  
  
  METHODS
  The human BM endothelial cell line (BMEC) and primary human BM endothelial cells were analyzed for expression of Notch ligands and the ability to expand hematopoietic progenitors in an in vitro coculture system. In vivo experiments were carried out to identify modulation of Notch signaling in BM endothelial and hematopoietic cells in mice challenged with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS), or in Tie2-tmTNF-alpha transgenic mice characterized by constitutive TNF-alpha activation.
  
  
  RESULTS
  BM endothelial cells were found to express Jagged ligands and to greatly support progenitor's colony-forming ability. This effect was markedly decreased by Notch antagonists and augmented by increasing levels of Jagged2. Physiologic upregulation of Jagged2 expression on BMEC was observed upon TNF-alpha activation. Injection of TNF-alpha or LPS upregulated three- to fourfold Jagged2 expression on murine BM endothelial cells in vivo and resulted in increased Notch activation on murine hematopoietic stem/progenitor cells. Similarly, constitutive activation of endothelial cells in Tie2-tmTNF-alpha mice was characterized by increased expression of Jagged2 and by augmented Notch activation on hematopoietic stem/progenitor cells.
  
  
  CONCLUSIONS
  Our results provide the first evidence that BM endothelial cells promote expansion of hematopoietic progenitor cells by a Notch-dependent mechanism and that TNF-alpha and LPS can modulate the levels of Notch ligand expression and Notch activation in the BM microenvironment in vivo.
authors.affiliation: Center of Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass., USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Fernandez
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Angelo
authors.initials: A
authors.lastname: Chora
authors.forename: Jacquenilson
authors.initials: J
authors.lastname: Fernandes
authors.forename: Christin
authors.initials: C
authors.lastname: Mumaw
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cruz
authors.forename: Karen
authors.initials: K
authors.lastname: Pollok
authors.forename: Filipa
authors.initials: F
authors.lastname: Cristina
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Price
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ferkowicz
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Matthias
authors.initials: M
authors.lastname: Clauss
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Cardoso
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000098:blood supply / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072101:Jagged-2 Protein; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C490504:JAG2 protein, human; D000072101:Jagged-2 Protein; D008024:Ligands; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051880:Receptors, Notch; D014409:Tumor Necrosis Factor-alpha