Brain Advance Access published online on July 16, 2009
Brain, doi:10.1093/brain/awp174
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Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms
1 Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland 2 Neuroimmunology Unit-DIBIT2 and Institute of Experimental Neurology, San Raffaele Scientific Institute, Via Olgettina 58, I-20132 Milan, Italy 3 Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Via Olgettina 58, I-20132 Milan, Italy 4 Institute of Anatomy, University Park, DK-8000 Aarhus, Denmark 5 Department of Neurology, University Hospital, University of Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany
Correspondence to:
Prof. Dr Dirk M. Hermann, Chair of Vascular Neurology, Dementia and Ageing Disorders, Department of Neurology, University Hospital Essen, Hufelandstr. 55, D-45122 Essen, Germany, E-mail: dirk.hermann{at}uk-essen.de
Recent evidence suggests that neural stem/precursor cells (NPCs) promote recovery in animal models with delayed neuronal death via a number of indirect bystander effects. A comprehensive knowledge of how transplanted NPCs exert their therapeutic effects is still lacking. Here, we investigated the effects of a delayed transplantation of adult syngenic NPCs—injected intravenously 72 h after transient middle cerebral artery occlusion—on neurological recovery, histopathology and gene expression. NPC-transplanted mice showed a significantly improved recovery from 18 days post-transplantation (dpt) onwards, which persisted throughout the study. A small percentage of injected NPCs accumulated in the brain, integrating mainly in the infarct boundary zone, where most of the NPCs remained undifferentiated up to 30 dpt. Histopathological analysis revealed a hitherto unreported very delayed neuroprotective effect of NPCs, becoming evident at 10 and 30 dpt. Tissue survival was associated with downregulation of markers of inflammation, glial scar formation and neuronal apoptotic death at both mRNA and protein levels. Our data highlight the relevance of very delayed degenerative processes in the stroke brain that are intimately associated with inflammatory and glial responses. These processes may efficaciously be antagonized by (stem) cell-based strategies at time-points far beyond established therapeutic windows for pharmacological neuroprotection.
Key Words: stroke; neural stem/precursor cells; transplantation; inflammation; gliosis
Abbreviations: CC, corpus callosum; CNS, central nervous system; dpt, days post-transplantation; i.v., intravenously; LDF, laser Doppler flow; MCAO, middle cerebral artery occlusion; NPCs, neural stem/precursor cells
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Received December 17, 2008. Revised May 15, 2009. Accepted May 21, 2009.
*These authors contributed equally to this work.
Present address: CNS Repair Unit-DIBIT2, and Institute of Experimental Neurology, San Raffaele Scientific Institute, Via Olgettina 58, I-20132 Milan, Italy Correspondence to: Prof. Dr Dirk M. Hermann, Chair of Vascular Neurology, Dementia and Ageing Disorders, Department of Neurology, University Hospital Essen, Hufelandstr. 55, D-45122 Essen, Germany E-mail: dirk.hermann{at}uk-essen.de