Intracerebroventricular Transplantation ofEx VivoExpanded Endothelial Colony-Forming Cells Restores Blood–Brain Barrier Integrity and Promotes Angiogenesis of Mice with Traumatic Brain Injury

Abstract

Endothelial progenitor cells (EPCs) play a key role in tissue repair and regeneration. Previous studies have shown a positive correlation between the number of circulating EPCs and clinical outcomes of patients with traumatic brain injury (TBI). A recent study has further shown that intravenous infusion of human umbilical cord blood-derived endothelial colony-forming cells (ECFCs) improves outcomes of mice subjected to experimental TBI. This follow-up study was designed to determine whether intracerebroventricular (i.c.v.) infusion of ECFCs, which may reduce systemic effects of these cells, could repair the blood-brain barrier (BBB) and promote angiogenesis of mice with TBI. Adult nude mice were exposed to fluid percussion injury and transplanted i.c.v. with ECFCs on day 1 post-TBI. These ECFCs were detected at the TBI zone 3 days after transplantation by SP-DiIC18(3) and fluorescence in situ hybridization. Mice with ECFCs transplant had reduced Evans blue extravasation and brain water content, increased expression of ZO-1 and claudin-5, and showed a higher expression of angiopoietin 1. Consistent with the previous report, mice with ECFCs transplant had also increased microvascular density. Modified neurological severity score and Morris water maze test indicated significant improvements in motor ability, spatial acquisition and reference memory in mice receiving ECFCs, compared to those receiving saline. These data demonstrate the beneficial effects of ECFC transplant on BBB integrity and angiogenesis in mice with TBI.

Brain-derived microparticles induce systemic coagulation in a murine model of traumatic brain injury

“…33 Briefly, a mouse was anesthetized by ketamine and xylazine (1 mg and 0.1 mg/10 g) on a ventilator (Harvard Apparatus, Hollistone, MA) and constrained to a platform to surgically expose the skull. A 3-mm-diameter hole was drilled into the skull (2.0-mm posterior from the bregma and 2.0-mm lateral to the sagittal suture) with the dura matter intact.…”

Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony–forming cells

“…ECFCs have shown promise for tissue regeneration. In mouse vascular injury models, they are rapidly recruited to the site of vascular injury or tissue ischemia after intravenous injection, where they initiate a vasculogenic response 8 , and they have been reported to enhance vascular repair and improve blood flow after myocardial infarction 9 , stroke 3,10 , ischemic retinopathy 2 and ischemic limb injury 8,11 , and to engraft and re-endothelialize denuded vascular segments or implanted grafts 12 . In elderly patients and subjects with peripheral arterial disease (PAD) and critical limb ischemia, ECFCs may become prone to replicative senescence, reducing their reparative potential.…”

Endothelial Progenitor Cells Physiology and Metabolic Plasticity in Brain Angiogenesis and Blood-Brain Barrier Modeling

“…At the same time, there is a growing evidence that EPC might serve as a therapeutic tool for a number of CNS pathologies including stroke, neurodevelopmental disorders, and neurodegeneration (Castillo-Melendez et al, 2013; Fukuda et al, 2013; Zhao et al, 2013). Very promising data have been obtained in the application of EPC for BBB repair in vivo (Huang et al, 2013b). However, application of EPC into routine neurological clinical practice is hampered by poor understanding the mechanisms underlying EPC homing at CNS and EPC-mediated cell-to-cell communications in cerebral microvessels within the NVU.…”