Early transient presence of implanted bone marrow stem cells reduces lesion size after cerebral ischaemia in adult rats.
OBJECTIVE
Previous studies on the therapeutic time window for intravascular administration of bone marrow stem cells (BMSCs) after stroke have shown that early intervention (from 3 h after onset) in the middle cerebral artery occlusion (MCAO) rat model is the most effective approach to reduce ischaemic lesion size. We have confirmed these observations but noticed that 2 weeks after transplantation, almost none of the grafted BMSCs could be detected in or around the lesion. The present experiments aimed to assess the fate and kinetics of intravascularly injected BMSCs shortly after administration in correlation to the development of the ischaemic lesion after MCAO.


METHODS
We administered a syngeneic suspension of complete (haematopoietic and mesenchymal) BMSCs via the carotid artery to rats at 2 h after MCAO onset. We examined the distribution and tissue location of BMSCs within the first 24 h after arterial administration by perfusion-fixating rats and performing immunohistochemical analysis at different time points.


RESULTS
The vast majority (>95%) of BMSCs appeared to become trapped in the spleen shortly after injection. Six hours after implantation, together with the appearance of activated microglia, the first BMSCs could be detected in and around the lesion; their number gradually increased during the first 12 h after implantation but started to decrease at 24 h. The implanted BMSCs were surrounded by activated and phagocytotic microglia.


CONCLUSIONS
Our results show that ischaemic lesion size reduction can already be achieved by the early transient presence at the lesion site of intravascularly implanted BMSCs, possibly mediated via activated microglia.
Keimpema
E
E
Department of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands.
Fokkens
M R
MR
Nagy
Z
Z
Agoston
V
V
Luiten
P G M
PG
Nyakas
C
C
Boddeke
H W G M
HW
Copray
J C V M
JC
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000503:physiopathology; D002545:Brain Ischemia / Q000628:therapy*; D002339:Carotid Arteries; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000628:therapy; D007269:Injections, Intra-Arterial; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology; D017628:Microglia / Q000502:physiology; D010587:Phagocytosis; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000502:physiology; D020521:Stroke / Q000628:therapy