http://stroke.ahajournals.org/content/44/12/3473.abstract?etoc
- Hiroto Ishikawa, MD, PhD;
- Naoki Tajiri, PT, PhD;
- Kazutaka Shinozuka, PhD;
- Julie Vasconcellos, BS;
- Yuji Kaneko, PhD;
- Hong J. Lee, PhD;
- Osamu Mimura, MD, PhD;
- Mari Dezawa, MD, PhD;
- Seung U. Kim, MD, PhD;
- Cesar V. Borlongan, PhD
+ Author Affiliations
- Correspondence to Cesar V. Borlongan, PhD, Department of Neurosurgery and Brain Repair, University of South Florida, 12901 Bruce B. Downs Blvd MDC78, Tampa, FL 33612. E-mail cborlong@health.usf.edu
Abstract
Background and Purpose—Despite
the reported functional recovery in transplanted stroke models and
patients, the mechanism of action underlying stem
cell therapy remains not well understood.
Here, we examined the role of stem cell–mediated vascular repair in
stroke.
Methods—Adult rats
were exposed to transient occlusion of the middle cerebral artery and 3
hours later randomly stereotaxically transplantated
with 100K, 200K, or 400K human cerebral
endothelial cell 6 viable cells or vehicle. Animals underwent
neurological examination
and motor test up to day 7 after
transplantation then euthanized for immunostaining against neuronal,
vascular, and specific
human antigens. A parallel in vitro study
cocultured rat primary neuronal cells with human cerebral endothelial
cell 6 under
oxygen-glucose deprivation and treated with
vascular endothelial growth factor (VEGF) and anti-VEGF.
Results—Stroke
animals that received vehicle infusion displayed typical occlusion of
the middle cerebral artery–induced behavioral
impairments that were dose-dependently
reduced in transplanted stroke animals at days 3 and 7 after
transplantation and accompanied
by increased expression of host neuronal and
vascular markers adjacent to the transplanted cells. Some transplanted
cells
showed a microvascular phenotype and
juxtaposed to the host vasculature. Infarct volume in transplanted
stroke animals was
significantly smaller than vehicle-infused
stroke animals. Moreover, rat neurons cocultured with human cerebral
endothelial
cell 6 or treated with VEGF exhibited
significantly less oxygen-glucose deprivation–induced cell death that
was blocked by
anti-VEGF treatment.
Conclusions—We
found attenuation of behavioral and histological deficits coupled with
robust vasculogenesis and neurogenesis in endothelial
cell–transplanted stroke animals, suggesting
that targeting vascular repair sets in motion a regenerative process in
experimental
stroke possibly via the VEGF pathway.
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