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Brain Advance Access published online on December 20, 2007
Brain, doi:10.1093/brain/awm306
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke

Soon-Tae Lee1,2,3,*, Kon Chu1,2,*, Keun-Hwa Jung1,2,4, Se-Jeong Kim1, Dong-Hyun Kim1, Kyung-Mook Kang1, Nan Hyung Hong1, Jin-Hee Kim1,2, Jae-Joon Ban1, Hee-Kwon Park1,2, Seung U. Kim5,6, Chung-Gyu Park7, Sang Kun Lee1,2, Manho Kim1,2 and Jae-Kyu Roh1,2

1Stroke & Stem Cell Laboratory, Clinical Research Institute, Stem Cell Research Center, Department of Neurology, Seoul National University Hospital, 2Program in Neuroscience, Neuroscience Research Institute of SNUMRC, Seoul National University, 3Program in Public Health Service, Seoul National Hospital, 4Department of Epidemic Intelligence Service, Korea Center for Disease Control and Prevention, Seoul, 5Institute for Regenerative Medicine, Gachon Medical University, Inchon, South Korea, 6Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, Canada and 7Department of Microbiology and Immunology, Xenotransplantation Research Center, Transplantation Research Institute, Tumor Immunity Medical Research Center, Seoul National University, Seoul, South Korea

Correspondence to: Jae-Kyu Roh, MD, PhD, Department of Neurology, Seoul National University Hospital, 28, Yongon-Dong, Chongro-Gu, Seoul, 110-744, Republic of Korea E-mail: rohjk{at}snu.ac.kr

Neural stem cell (NSC) transplantation has been investigated as a means to reconstitute the damaged brain after stroke. In this study, however, we investigated the effect on acute cerebral and peripheral inflammation after intracerebral haemorrhage (ICH). NSCs (H1 clone) from fetal human brain were injected intravenously (NSCs-iv, 5 million cells) or intracerebrally (NSCs-ic, 1 million cells) at 2 or 24 h after collagenase-induced ICH in a rat model. Only NSCs-iv-2 h resulted in fewer initial neurologic deteriorations and reduced brain oedema formation, inflammatory infiltrations (OX-42, myeloperoxidase) and apoptosis (activated caspase-3, TUNEL) compared to the vehicle-injected control animals. Rat neurosphere-iv-2 h, but not human fibroblast-iv-2 h, also reduced the brain oedema and the initial neurologic deficits. Human NSCs-iv-2 h also attenuated both cerebral and splenic activations of tumour necrosis factor-alpha (TNF-{alpha}), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-{kappa}B). However, we observed only a few stem cells in brain sections of the NSCs-iv-2 h group; in the main, they were detected in marginal zone of spleens. To investigate whether NSCs interact with spleen to reduce cerebral inflammation, we performed a splenectomy prior to ICH induction, which eliminated the effect of NSCs-iv-2 h transplantation on brain water content and inflammatory infiltrations. NSCs also inhibited in vitro macrophage activations after lipopolysaccharide stimulation in a cell-to-cell contact dependent manner. In summary, early intravenous NSC injection displayed anti-inflammatory functionality that promoted neuroprotection, mainly by interrupting splenic inflammatory responses after ICH.

Key Words: neural stem cell; spleen; cerebral inflammation; intracerebral haemorrhage; macrophage

Abbreviations: bFGF, basic fibroblast growth factor; ChAT, choline acetyltransferase; DMEM, Dulbecco's Modified Eagle's Medium; EAE, experimental autoimmune encephalitis; EGF, epidermal growth factor; GFAP, glial fibrillary acidic protein; HPF, high power field; ICH, intracerebral haemorrhage; IL, interleukin; LPS, lipopolysaccharide; MPO, myeloperoxidase; MLPT, modified limb placing test; NF-{kappa}B, nuclear factor-kappaB; NSCs, neural stem cells; SDF-1{alpha}, stromal cell derived factor-1alpha; TGF, tumour growth factor; TNF-{alpha}, tumour necrosis factor-alpha; TUNEL, terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling

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Received June 25, 2007. Revised November 15, 2007. Accepted November 26, 2007.

*These authors contributed equally to this work.


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