title: Cord blood-derived endothelial colony-forming cell function is disrupted in congenital diaphragmatic hernia.
abstract: Vascular growth is necessary for normal lung development. Although endothelial progenitor cells (EPCs) play an important role in vascularization, little is known about EPC function in congenital diaphragmatic hernia (CDH), a severe neonatal condition that is associated with pulmonary hypoplasia. We hypothesized that the function of endothelial colony-forming cells (ECFCs), a type of EPC, is impaired in CDH. Cord blood (CB) was collected from full-term CDH patients and healthy controls. We assessed CB progenitor cell populations as well as plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1α (SDF1α) levels. CB ECFC clonogenicity; growth kinetics; migration; production of VEGF, SDF1α, and nitric oxide (NO); vasculogenic capacity; and mRNA expression of VEGF-A, fms-related tyrosine kinase 1 (FLT1), kinase insert domain receptor (KDR), nitric oxide synthase (NOS) 1-3, SDF1, and chemokine (C-X-C motif) receptor 4 (CXCR4) were also assessed. Compared with controls, CB ECFCs were decreased in CDH. CDH ECFCs had reduced potential for self-renewal, clonogenicity, proliferation, and migration. Their capacity for NO production was enhanced but their response to VEGF was blunted in CDH ECFCs. In vivo potential for de novo vasculogenesis was reduced in CDH ECFCs. There was no difference in CB plasma VEGF and SDF1α concentrations, VEGF and SDF1α production by ECFCs, and ECFC mRNA expression of VEGF-A, FLT1, KDR, NOS1-3, SDF1, and CXCR4 between CDH and control subjects. In conclusion, CB ECFC function is disrupted in CDH, but these changes may be caused by mechanisms other than alteration of VEGF-NO and SDF1-CXCR4 signaling.
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan; Department of Reproductive Biology, National Institute for Child Health and Development, Tokyo, Japan; Division of Neonatology, Center for Maternal-Fetal and Neonatal Medicine, National Center for Child Health and Development, Tokyo, Japan; fujinaga-h@ncchd.go.jp.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Fujinaga
authors.affiliation: Department of Reproductive Biology, National Institute for Child Health and Development, Tokyo, Japan;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Fujinaga
authors.affiliation: Department of Human Genetics, National Institute for Child Health and Development, Tokyo, Japan; and.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Department of Systems BioMedicine, National Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Systems BioMedicine, National Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Moe
authors.initials: M
authors.lastname: Tamano
authors.affiliation: Department of Systems BioMedicine, National Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Terao
authors.affiliation: Department of Systems BioMedicine, National Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Takada
authors.affiliation: Division of Neonatology, Center for Maternal-Fetal and Neonatal Medicine, National Center for Child Health and Development, Tokyo, Japan;
authors.forename: Yushi
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Reproductive Biology, National Institute for Child Health and Development, Tokyo, Japan;
authors.forename: Akihiro
authors.initials: A
authors.lastname: Umezawa
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan;
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
mesh_terms: D016022:Case-Control Studies; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000097:blood; D066026:Endothelial Progenitor Cells / Q000502:physiology*; D005312:Fetal Blood; D065630:Hernias, Diaphragmatic, Congenital / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007231:Infant, Newborn; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D054377:Chemokine CXCL12; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide
keywords: congenital diaphragmatic hernia; cord blood; endothelial colony-forming cells; endothelial progenitor cells