Elevated brain derived neurotrophic factor levels in plasma reflect in vivo functional viability of infused mesenchymal stem cells for stroke in rats.
BACKGROUND
Intravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow elicits functional recovery in rat stroke models and clinical studies in patients are ongoing. Brain derived neurotrophic factor (BDNF) is a neurotrophic factor produced by MSCs and may contribute to their therapeutic efficacy. The purpose of the current study was to determine if BDNF is elevated in infarcted brain and in which compartment of blood (plasma or serum) after intravenous MSC infusion in a middle cerebral artery occlusion (MCAO) model in the rat.


METHODS
In rats, a permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament and MSCs were intravenously administered 6 h after right MCAO induction. Enzyme-linked immunosorbent assay (ELISA) analysis of brain, serum and plasma BDNF were performed after the MSC infusion following the MCAO induction. Lesion volume was assessed using magnetic resonance imaging. Functional outcome was assessed using the Limb Placement Test.


RESULTS
Infused MSCs reduced lesion volume and elicited functional improvement compared to the vehicle infused group. ELISA analysis of the MSC treated group revealed an increase BDNF levels in the infarcted hemisphere of the brain and plasma, but not in serum. The MSC group showed a greater increase in BDNF levels than sham control. In the MSC group, the expression of increased plasma BDNF levels correlated with increased brain BDNF levels.


CONCLUSIONS
These results support the hypothesis that BDNF levels in plasma, but not serum, may be more appropriate to detect circulating BDNF in vivo following MSC infusion in a cerebral infarction rat model of ischemic stroke. Further, plasma BDNF might reflect in vivo functional viability of infused MSCs after stroke.
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Hideyuki
H
Nakamura
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Yuichi
Y
Sasaki
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan - msasaki@sapmed.ac.jp.|Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.|Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, West Haven, CT, USA.
Masanori
M
Sasaki
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Yuko
Y
Kataoka-Sasaki
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Shinichi
S
Oka
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Masahito
M
Nakazaki
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Takahiro
T
Namioka
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Ai
A
Namioka
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Rie
R
Onodera
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Junpei
J
Suzuki
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Hiroshi
H
Nagahama
Department of Neurosurgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Takeshi
T
Mikami
Department of Neurosurgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Masahiko
M
Wanibuchi
Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.|Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, West Haven, CT, USA.
Jeffery D
JD
Kocsis
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.|Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, West Haven, CT, USA.
Osamu
O
Honmou
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood*; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D010949:Plasma; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000097:blood* / Q000209:etiology / Q000628:therapy*
C000628854:Bdnf protein, rat; D019208:Brain-Derived Neurotrophic Factor