title: Jagged-1 Signaling in the Bone Marrow Microenvironment Promotes Endothelial Progenitor Cell Expansion and Commitment of CD133+ Human Cord Blood Cells for Postnatal Vasculogenesis.
abstract: Notch signaling is involved in cell fate decisions during murine vascular development and hematopoiesis in the microenvironment of bone marrow. To investigate the close relationship between hematopoietic stem cells and human endothelial progenitor cells (EPCs) in the bone marrow niche, we examined the effects of Notch signals [Jagged-1 and Delta-like ligand (Dll)-1] on the proliferation and differentiation of human CD133+ cell-derived EPCs. We established stromal systems using HESS-5 murine bone marrow cells transfected with human Jagged-1 (hJagged-1) or human Dll-1 (hDll-1). CD133+ cord blood cells were co-cultured with the stromal cells for 7 days, and then their proliferation, differentiation, and EPC colony formation was evaluated. We found that hJagged-1 induced the proliferation and differentiation of CD133+ cord blood EPCs. In contrast, hDll-1 had little effect. CD133+ cells stimulated by hJagged-1 differentiated into CD31+/KDR+ cells, expressed vascular endothelial growth factor-A, and showed enhanced EPC colony formation compared with CD133+ cells stimulated by hDll-1. To evaluate the angiogenic properties of hJagged-1- and hDll-1-stimulated EPCs in vivo, we transplanted these cells into the ischemic hindlimbs of nude mice. Transplantation of EPCs stimulated by hJagged-1, but not hDll-1, increased regional blood flow and capillary density in ischemic hindlimb muscles. This is the first study to show that human Notch signaling influences EPC proliferation and differentiation in the bone marrow microenvironment. Human Jagged-1 induced the proliferation and differentiation of CD133+ cord blood progenitors compared with hDll-1. Thus, hJagged-1 signaling in the bone marrow niche may be used to expand EPCs for therapeutic angiogenesis.
authors.affiliation: Department of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Japan.|Department of Pediatrics and Child Health, Nihon University school of Medicine, Tokyo, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Ishige-Wada
authors.affiliation: Department of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Sang-Mo
authors.initials: SM
authors.lastname: Kwon
authors.affiliation: Department of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Eguchi
authors.affiliation: Department of Immunology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Hozumi
authors.affiliation: Department of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwaguro
authors.affiliation: Division of Cell Regeneration and Transplantation, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.affiliation: Department of Pediatrics and Child Health, Nihon University school of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Mugishima
authors.affiliation: Department of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Haruchika
authors.initials: H
authors.lastname: Masuda
authors.affiliation: Department of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics*; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D066026:Endothelial Progenitor Cells / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006614:Hindlimb / Q000254:growth & development; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics*; D055153:Stem Cell Niche / Q000235:genetics; D033581:Stem Cell Transplantation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D000071916:AC133 Antigen; D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2