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

被引:327
作者
Lee, Soon-Tae [1 ,2 ,3 ]
Chu, Kon [1 ,2 ]
Jung, Keun-Hwa [1 ,2 ,4 ]
Kim, Se-Jeong [1 ]
Kim, Dong-Hyun [1 ]
Kang, Kyung-Mook [1 ]
Hong, Nan Hyung [1 ]
Kim, Jin-Hee [1 ,2 ]
Ban, Jae-Joon [1 ]
Park, Hee-Kwon [1 ,2 ]
Kim, Seung U. [5 ,6 ]
Park, Chung-Gyu [7 ]
Lee, Sang Kun [1 ,2 ]
Kim, Manho [1 ,2 ]
Roh, Jae-Kyu [1 ,2 ]
机构
[1] Seoul Natl Univ Hosp, Dept Neurol, Stem Cell Res Ctr, Clin Res Inst,Stroke & Stem Cell Lab, Seoul 110744, South Korea
[2] Seoul Natl Univ, Neurosci Res Inst, SNUMRC, Program Neurosci, Seoul 151, South Korea
[3] Seoul Natl Hosp, Program Publ Hlth Serv, Seoul, South Korea
[4] Korea Ctr Dis Control & Prevent, Dept Epidem Intelligence Serv, Seoul, South Korea
[5] Gachon Med Univ, Inst Regenerat Med, Inchon, South Korea
[6] Univ British Columbia, UBC Hosp, Dept Med, Div Neurol, Vancouver, BC V5Z 1M9, Canada
[7] Seoul Natl Univ, Tumor Immun Med Res Ctr, Transplantat Res Inst, Dept Microbiol & Immunol,Xenotransplantat Res Ctr, Seoul, South Korea
关键词
neural stem cell; spleen; cerebral inflammation; intracerebral haemorrhage; macrophage;
D O I
10.1093/brain/awm306
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 (HI 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.
引用
收藏
页码:616 / 629
页数:14
相关论文
共 69 条
[1]   Cytokines and acute neurodegeneration [J].
Allan, SM ;
Rothwell, NJ .
NATURE REVIEWS NEUROSCIENCE, 2001, 2 (10) :734-744
[2]   New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies [J].
Aronowski, J ;
Hall, CE .
NEUROLOGICAL RESEARCH, 2005, 27 (03) :268-279
[3]   Role for matrix metalloproteinase 9 after focal cerebral ischemia, effects of gene knockout and enzyme inhibition with BB-94 [J].
Asahi, M ;
Asahi, K ;
Jung, JC ;
del Zoppo, GJ ;
Fini, ME ;
Lo, EH .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2000, 20 (12) :1681-1689
[4]  
Barker Roger A, 2004, NeuroRx, V1, P472, DOI 10.1007/BF03206631
[5]   Inflammatory mediators and stroke: New opportunities for novel therapeutics [J].
Barone, FC ;
Feuerstein, GZ .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 1999, 19 (08) :819-834
[6]   Molecular signatures of brain injury after intracerebral hemorrhage [J].
Castillo, J ;
Dávalos, A ;
Alvarez-Sabín, J ;
Pumar, JM ;
Leira, R ;
Silva, Y ;
Montaner, J ;
Kase, CS .
NEUROLOGY, 2002, 58 (04) :624-629
[7]   Infection after acute ischemic stroke - A manifestation of brain-induced immunodepression [J].
Chamorro, Angel ;
Urra, Xabier ;
Planas, Anna M. .
STROKE, 2007, 38 (03) :1097-1103
[8]   Use of a spectrophotometric hemoglobin assay to objectively quantify intracerebral hemorrhage in mice [J].
Choudhri, TF ;
Hoh, BL ;
Solomon, RA ;
Connolly, ES ;
Pinsky, DJ .
STROKE, 1997, 28 (11) :2296-2302
[9]   Combined treatment of vascular endothelial growth factor and human neural stem cells in experimental focal cerebral ischemia [J].
Chu, K ;
Park, KI ;
Lee, ST ;
Jung, KH ;
Ko, SY ;
Kang, L ;
Sinn, DI ;
Lee, YS ;
Kim, SU ;
Kim, M ;
Roh, JK .
NEUROSCIENCE RESEARCH, 2005, 53 (04) :384-390
[10]   Distribution and in situ proliferation patterns of intravenously injected immortalized human neural stem-like cells in rats with focal cerebral ischemia [J].
Chu, K ;
Kim, M ;
Chae, SH ;
Jeong, SW ;
Kang, KS ;
Jung, KH ;
Kim, J ;
Kim, YJ ;
Kang, L ;
Kim, SU ;
Yoon, BW .
NEUROSCIENCE RESEARCH, 2004, 50 (04) :459-465