title: Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms.
abstract: 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.
authors.affiliation: Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Bacigaluppi
authors.forename: Stefano
authors.initials: S
authors.lastname: Pluchino
authors.forename: Luca
authors.initials: L
authors.lastname: Peruzzotti-Jametti
authors.forename: Luca Peruzzotti
authors.initials: LP
authors.lastname: Jametti
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Kilic
authors.forename: Ulkan
authors.initials: U
authors.lastname: Kilic
authors.forename: Giuliana
authors.initials: G
authors.lastname: Salani
authors.forename: Elena
authors.initials: E
authors.lastname: Brambilla
authors.forename: Mark J
authors.initials: MJ
authors.lastname: West
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001284:Atrophy / Q000517:prevention & control; D001921:Brain / Q000378:metabolism; D002470:Cell Survival; D002921:Cicatrix / Q000517:prevention & control; D003337:Corpus Callosum / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000637:transplantation*; D033581:Stem Cell Transplantation / Q000379:methods*; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000628:therapy*