Abstract
BackgroundTreatment with neural stem cells represents a potential strategy to improve functional recovery of post-ischemic cerebral injury. The potential benefit of such treatment in acute phases of human ischemic stroke depends on the therapeutic viability of a systemic vascular delivery route. In spite of the large number of reports on the beneficial effects of intracerebral stem cells injection in experimental stroke, very few studies demonstrated the effectiveness of the systemic intravenous delivery approach.Metodology/Principal FindingsWe utilized a novel in vitro model of transient focal ischemia to analyze the brain distribution of neurosphere-derived cells (NCs) in the early 3 hours that follow transient occlusion of the medial cerebral artery (MCA). NCs obtained from newborn C57/BL6 mice are immature cells with self-renewal properties that could differentiate into neurons, astrocytes and oligodendrocytes. MCA occlusion for 30 minutes in the in vitro isolated guinea pig brain preparation was followed by arterial perfusion with 1×106 NCs charged with a green fluorescent dye, either immediately or 60 minutes after reperfusion onset. Changes in extracellular pH and K+ concentration during and after MCAO were measured through ion-sensitive electrodes.Conclusion/SignificanceIt is demonstrated that NCs injected through the vascular system do not accumulate in the ischemic core and preferentially distribute in non-ischemic areas, identified by combined electrophysiological and morphological techniques. Direct measurements of extracellular brain ions during and after MCA occlusion suggest that anoxia-induced tissue changes, such as extracellular acidosis, may prevent NCs from entering the ischemic area in our in vitro model of transitory focal ischemia and reperfusion suggesting a role played by the surrounding microenviroment in driving NCs outside the ischemic core. These findings strongly suggest that the potential beneficial effect of NCs in experimental focal brain ischemia is not strictly dependent on their homing into the ischemic region, but rather through a bystander mechanism possibly mediated by the release of neuroprotective factors in the peri-infarct region.
Highlights
Neuronal stem cells are immature cells with self-renewal potentials that are able to differentiate into neurons, astrocytes and oligodendrocytes [1,2]
Direct measurements of extracellular brain ions during and after medial cerebral artery (MCA) occlusion suggest that anoxia-induced tissue changes, such as extracellular acidosis, may prevent neurosphere-derived cells (NCs) from entering the ischemic area in our in vitro model of transitory focal ischemia and reperfusion suggesting a role played by the surrounding microenviroment in driving NCs outside the ischemic core. These findings strongly suggest that the potential beneficial effect of NCs in experimental focal brain ischemia is not strictly dependent on their homing into the ischemic region, but rather through a bystander mechanism possibly mediated by the release of neuroprotective factors in the peri-infarct region
In control experiments (n = 3) no occlusion of MCA was performed and NCs injection followed the time of perfusion described either in the protocol 1 (n = 2) or protocol 2 (n = 1)
Summary
Neuronal stem cells are immature cells with self-renewal potentials that are able to differentiate into neurons, astrocytes and oligodendrocytes [1,2]. A recent report demonstrated that the functional improvement of open field performances and the neuronal survival in a mouse model of transient occlusion of the medial cerebral artery (MCA) is independent on the persistence of intracerebroventricularly injected neurosphere-derived cells (NCs) in the brain parenchyma [13]. These findings strongly suggest that the favorable effects of NCs may be due to the release of neuroprotective factors in the ischemic microenvironment, rather to the replacement of damaged neurons. Changes in extracellular pH and K+ concentration during and after MCAO were measured through ion-sensitive electrodes
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