Hyojin Kim1, Lan Huang2, Paul J Critser3, Zhenyun Yang3, Rebecca J Chan3, Lin Wang4, Nadia Carlesso4, Sherry L Voytik-Harbin5, Irwin D Bernstein6, Mervin C Yoder7. 1. 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. 2. 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. 3. 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. 4. 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. 5. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA. 6. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 7. 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.
Abstract
BACKGROUND AIMS: 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.
BACKGROUND AIMS: 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.
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