Abstract
Cell-therapies that invoke pleiotropic mechanisms may facilitate functional recovery in stroke patients. We hypothesized that a cell therapy using microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2 microglia. We first delineated changes in angiogenesis and axonal outgrowth in the ischemic cortex using rats. We found that slight angiogenesis without axonal outgrowth were activated at the border area within the ischemic core from 7 to 14 days after ischemia. Next, we demonstrated that administration of primary microglia preconditioned by 18 hours of OGD at 7 days prompted functional recovery at 28 days after focal cerebral ischemia compared to control therapies by marked secretion of remodelling factors such as vascular endothelial growth factor, matrix metalloproteinase-9, and transforming growth factor-β polarized to M2 microglia in vitro/vivo. In conclusion, intravascular administration of M2 microglia preconditioned by optimal OGD may be a novel therapeutic strategy against ischemic stroke.
Highlights
Mononuclear stem cells among patients with ischemic stroke[15]
To determine the detailed localization and temporal changes of angiogenesis after transient focal cerebral ischemia, we performed immunofluorescence staining against the ischemic cortex of Sprague-Dawley rats using an antibody against the endothelial and angiogenesis marker, cluster of differentiation (CD)[31] (Fig. 1A and B)
Confocal microscopic studies revealed that the immunoreactivity for CD31 volume per unit volume on the border area within the ischemic core defined as microtubule-associated protein 2 (MAP2)-negative area decreased at 1 day after cerebral ischemia and reached a minimum level at 3 days after cerebral ischemia compared to sham-operated rats (Fig. 1B)
Summary
Mononuclear stem cells among patients with ischemic stroke[15]. In addition, there remain several clinical concerns, including the efficiency with which bone marrow-derived cells cross the BBB16 and the technical safety of bone marrow-derived cell collection in patients who are undergoing anticoagulant or antiplatelet therapy for secondary prevention of stroke. We hypothesized that microglia preconditioned by oxygen-glucose deprivation (OGD) and administered intra-arterially may cross the BBB, secrete remodelling factors in the brain parenchyma, and exert pleiotropic therapeutic effects via the promotion of angiogenesis and axonal outgrowth against focal cerebral ischemia even in the subacute phase. To test this hypothesis, we first delineated temporal changes in angiogenesis and axonal outgrowth in the ischemic core and penumbra in a rat model of transient focal cerebral ischemia. We investigated whether primary microglia preconditioned by optimal OGD promoted functional recovery via enhancement of angiogenesis and axonal outgrowth after focal cerebral ischemia
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