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The Journal of Neuroscience, March 22, 2006, 26(12):3182-3191; doi:10.1523/JNEUROSCI.0156-06.2006

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Development/Plasticity/Repair
Chemokines Regulate the Migration of Neural Progenitors to Sites of Neuroinflammation

Abdelhak Belmadani, ^* Phuong B. Tran, ^* Dongjun Ren, and Richard J. Miller

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611

Correspondence should be addressed to Prof. Richard J. Miller, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, 303 East Chicago Avenue, Ward 8-296, Chicago, IL 60611. Email: r-miller10{at}northwestern.edu

Many studies have shown that transplanted or endogenous neural progenitor cells will migrate toward damaged areas of the brain. However, the mechanism underlying this effect is not clear. Here we report that, using hippocampal slice cultures, grafted neural progenitor cells (NPs) migrate toward areas of neuroinflammation and that chemokines are a major regulator of this process. Migration of NPs was observed after injecting an inflammatory stimulus into the area of the fimbria and transplanting enhanced green fluorescent protein (EGFP)-labeled NPs into the dentate gyrus of cultured hippocampal slices. Three to 7 d after transplantation, EGFP–NPs in control slices showed little tendency to migrate and had differentiated into neurons and glia. In contrast, in slices injected with inflammatory stimuli, EGFP–NPs migrated toward the site of the injection. NPs in these slices also survived less well. The inflammatory stimuli used were a combination of the cytokines tumor necrosis factor- and interferon-, the bacterial toxin lipopolysaccharide, the human immunodeficiency virus-1 coat protein glycoprotein 120, or a -amyloid-expressing adenovirus. We showed that these inflammatory stimuli increased the synthesis of numerous chemokines and cytokines by hippocampal slices. When EGFP–NPs from CC chemokine receptor CCR₂ knock-out mice were transplanted into slices, they exhibited little migration toward sites of inflammation. Similarly, wild-type EGFP–NPs exhibited little migration toward inflammatory sites when transplanted into slices prepared from monocyte chemoattractant protein-1 (MCP-1) knock-out mice. These data indicate that factors secreted by sites of neuroinflammation are attractive to neural progenitors and suggest that chemokines such as MCP-1 play an important role in this process.

Key words: CCR₂ receptors; MCP-1; migration; neural progenitors; neurogenesis; neuroinflammation; neural precursor

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Received July 29, 2005; revised Feb. 5, 2006; accepted Feb. 7, 2006.

Correspondence should be addressed to Prof. Richard J. Miller, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, 303 East Chicago Avenue, Ward 8-296, Chicago, IL 60611. Email: r-miller10{at}northwestern.edu

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