title: Notch ligand Delta-like 1 promotes in vivo vasculogenesis in human cord blood-derived endothelial colony forming cells.
abstract: OBJECTIVE
  Human cord blood (CB) is enriched in circulating endothelial colony forming cells (ECFCs) that display high proliferative potential and in vivo vessel forming ability. Because Notch signaling is critical for embryonic blood vessel formation in utero, we hypothesized that Notch pathway activation may enhance cultured ECFC vasculogenic properties in vivo.
  
  
  METHODS
  In vitro ECFC stimulation with an immobilized chimeric Notch ligand (Delta-like1(ext-IgG)) led to significant increases in the mRNA and protein levels of Notch regulated Hey2 and EphrinB2 that were blocked by treatment with γ-secretase inhibitor addition. However, Notch stimulated preconditioning in vitro failed to enhance ECFC vasculogenesis in vivo. In contrast, in vivo co-implantation of ECFCs with OP9-Delta-like 1 stromal cells that constitutively expressed the Notch ligand delta-like 1 resulted in enhanced Notch activated ECFC-derived increased vessel density and enlarged vessel area in vivo, an effect not induced by OP9 control stromal implantation.
  
  
  RESULTS
  This Notch activation was associated with diminished apoptosis in the exposed ECFC.
  
  
  CONCLUSIONS
  We conclude that Notch pathway activation in ECFC in vivo via co-implanted stromal cells expressing delta-like 1 promotes vasculogenesis and augments blood vessel formation via diminishing apoptosis of the implanted ECFC.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA; Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Critser
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Zhenyun
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Voytik-Harbin
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA. Electronic address: myoder@iu.edu.
authors.forename: Mervin C
authors.initials: MC
authors.lastname: Yoder
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology*; D006801:Humans; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D003094:Collagen
keywords: Notch ligand delta-like 1 (Dll1); OP9-Delta-like 1 stromal cells (OP9-DL1); apoptosis; endothelial colony forming cells (ECFCs); vasculogenesis