Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia.
Intravenous transplantation of human mesenchymal stem cells (hMSCs) expanded from adult bone marrow ameliorates functional deficits in rat cerebral infarction models. Several hypotheses to account for the therapeutic mechanisms have been suggested, but angiogenesis is thought to be of critical importance. Recently, we have reported the therapeutic benefits of hMSCs which have been transfected with the angiopoietin-1 gene in a rat permanent middle cerebral artery occlusion (MCAO) model. To potentially enhance the therapeutic effects of angiopoietin-1 gene-modified hMSC (Ang-hMSC), we transfected hMSCs with the angiopoietin-1 gene and the VEGF gene, and investigated whether the combination of Ang-1 and VEGF gene-modified hMSCs (Ang-VEGF-hMSC) contribute to functional recovery in a rat MCAO model. We induced MCAO using intraluminal vascular occlusion, and hMSCs, Ang-hMSCs, VEGF-hMSCs or Ang-VEGF-hMSCs were intravenously infused 6 h later. MRI and behavioral analyses revealed that rats receiving Ang-VEGF-hMSCs showed the greatest structural-functional recovery as compared to the other groups. These results suggest that intravenous administration of hMSCs transfected with the angiopoietin-1 and VEGF gene using a fiber-mutant adenovirus vector may represent a new strategy for the treatment of ischemia.
Toyama
Kentaro
K
Department of Neurosurgery, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.
Honmou
Osamu
O
Harada
Kuniaki
K
Suzuki
Junpei
J
Houkin
Kiyohiro
K
Hamada
Hirofumi
H
Kocsis
Jeffery D
JD
D042683:Angiopoietin-1 / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000235:genetics; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A