Abstract
IntroductionClinically, a good deal of injury from stroke results from ischemic-reperfusion. There is a loss of cerebral parenchyma and its associated cells, disruption of neuronal connections, compromise of the blood-brain barrier, and inflammation. We tested whether exogenously engrafted human neural stem cells could migrate rapidly and extensively to damaged regions, following transplantation into a neurogenic site where migration cues are already underway during stroke onset, then counteract a number of these pathological processes.MethodsOne day post-injury, we injected human neural stem cells (hNSCs) into the ipsilesional hippocampus of a mouse model of stroke with middle cerebral artery occlusion to induce focal ischemia followed by reperfusion (MCAO/R). The time frame for hNSC transplantation corresponded to upregulation of endogenous proinflammatory cytokines. We examined the effect of hNSC transplantation on pathological processes and behavioral dysfunction 48 hours post-injury.ResultsTwenty-four hours after transplantation, engrafted hNSCs had migrated extensively to the lesion, and infarct volume was reduced relative to MCAO/R controls. The behavioral deficits seen in MCAO/R controls were also significantly improved. Given this rapid response, we hypothesized that the mechanisms underlying therapeutic activity were anti-inflammatory rather than due to cell replacement. In support of this idea, in hNSC-transplanted mice we observed reduced microglial activation, decreased expression of proinflammatory factors (tumor necrosis factor-α, interleukin (IL)-6, IL-1β, monocyte chemotactic protein-1, macrophage inflammatory protein-1α) and adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), and amelioration of blood-brain barrier damage.ConclusionsWhile long-term effects of engrafted hNSCs on the amelioration of ischemic stroke-induced behavioral dysfunction in a rodent model have been reported, our study is the first to show rapid, beneficial impacts on behavioral function (within 24 hours) upon early delivery of hNSCs into the hippocampus.Electronic supplementary materialThe online version of this article (doi:10.1186/scrt519) contains supplementary material, which is available to authorized users.
Highlights
A good deal of injury from stroke results from ischemic-reperfusion
We evaluated how rapidly and efficiently transplanted human neural stem cells (hNSCs) migrated into the stroke lesion and determined their pathophysiology as it relates to blood-brain barrier (BBB) disruption, neuroinflammation and behavioral dysfunction
MCAO/R was performed in C57BL/6 J mice at time 0, and hNSCs were transplanted into the ipsilesional hippocampus 24 hours later
Summary
There is a loss of cerebral parenchyma and its associated cells, disruption of neuronal connections, compromise of the blood-brain barrier, and inflammation. Neural stem cells (NSCs) possess multiple actions that are potentially therapeutic. These include functional neural replacement in multiple central nervous system (CNS) regions [1], as well as bystander effects. Fast reperfusion contributes to secondary injury by disrupting cerebral microvascular endothelial cell tight junctions that constitute the blood-brain barrier (BBB) accompanied by neuronal death [7]. Compromise of the BBB in ischemic stroke may be mediated by multiple effectors, including growth factors, upregulation of endothelial-leukocyte adhesion molecules, inflammatory factors, matrix metalloproteinases, and disruption of tight junctions [8,9,10,11,12,13]
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