Journal Article

Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms

Marco Bacigaluppi, Stefano Pluchino, Luca Peruzzotti Jametti, Ertugrul Kilic, Ülkan Kilic, Giuliana Salani, Elena Brambilla, Mark J. West, Giancarlo Comi, Gianvito Martino and Dirk M. Hermann

in Brain

Published on behalf of The Guarantors of Brain

Volume 132, issue 8, pages 2239-2251
Published in print August 2009 | ISSN: 0006-8950
Published online July 2009 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awp174
Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms

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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.

Keywords: stroke; neural stem/precursor cells; transplantation; inflammation; gliosis

Journal Article.  6384 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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