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.

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

“…Third, ECFCs’ angiogenic behavior is typically compromised in the presence of cardiovascular risk factors that predispose to the onset of ischemic disorders; this further contributes to discouraging the use of circulating ECFCs for autologous cell therapy [ 15 , 59 , 110 , 115 ]. For instance, the frequency and/or vasoreparative potential of circulating ECFCs are remarkably reduced with CAD [ 120 ], aging [ 121 ], diabetes [ 122 ], abdominal aortic aneurysm [ 123 ], venous thromboembolic disease [ 124 ], congenital diaphragmatic hernia [ 125 ], systemic lupus erythematosus [ 126 ], and the pediatric Moyamoya disease (MMD) [ 127 ]. In addition, ECFCs’ angiogenic behaviour is impaired in patients affected by human immunodeficiency virus (HIV), which has long been associated with cardiovascular disorders [ 128 ].…”

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

“…34,35 Endothelial colonyforming cells derived from cord blood of CDH newborns have blunted responses to VEGF and high levels of nitric oxide production, as well as reduced potential for proliferation and migration, which suggests a reduced number of both VEGF receptors in endothelial cells of CDH newborns. 36 Krüppel-like factor 2 (KLF-2), a central regulator of endothelial function, is known to mediate the VEGF-induced EC maturation. 37 In lungs of nitrofen-exposed fetuses with CDH, KLF-2 is downregulated.…”

Congenital Diaphragmatic Hernia

“…Hernia altered in CDH infants, but the mechanism is unknown [114]. Russo et al reported the use of transplacental sildenafil rescues lung abnormalities in a rabbit model of CDH, improves vascular branching, and reduces pulmonary vascular resistance [115].…”