Intra-arterial cell transplantation provides timing-dependent cell distribution and functional recovery after stroke.
OBJECTIVE
Intra-arterial cell transplantation offers a novel therapeutic strategy for stroke; however, it remains unclear how the timing of cell administration affects cell distribution, brain repair processes, and functional recovery. Here, we investigate the hypothesis that the timing of cell transplantation changes the behavior of the cell graft and the host environment in a way that affects functional recovery.


METHODS
Rats received human mesenchymal stem cells via the internal carotid artery at 1, 4, or 7 days (D1, D4, or D7) after middle cerebral artery occlusion and reperfusion. Animals were euthanized at various time points to assess cell distribution, infiltration of activated microglia, expression of brain-derived neurotrophic factor, reactive astrocytes, angiogenesis, and functional recovery.


RESULTS
Human mesenchymal stem cells were widely distributed both in the peri-infarct and core in D1, and dominantly in the peri-infarct in D4. Very few cells were observed on D7. At day 7 poststroke, microglia activation was significantly suppressed in both the peri-infarct and core in D1, and predominantly in the peri-infarct in D4. At day 21 poststroke, brain-derived neurotrophic factor was widely distributed throughout the peri-infarct in D1 and D4, along with many reactive astrocytes and considerable angiogenesis. Motor function improved earlier in D1 and later in D4, but no recovery was obtained in D7.


CONCLUSIONS
Our results indicate that intra-arterial cell transplantation provides timing-dependent cell distribution and poststroke functional recovery via a combination of neuroprotection, reactive astrocyte enhancement, and angiogenesis.
Department of Neurosurgery, Nagasaki University School of Medicine, Nagasaki , Japan.
Shunsuke
S
Ishizaka
Nobutaka
N
Horie
Katsuya
K
Satoh
Yuhtaka
Y
Fukuda
Noriyuki
N
Nishida
Izumi
I
Nagata
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007269:Injections, Intra-Arterial; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology*; D020521:Stroke / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D020780:Matrix Metalloproteinase 9