| Abstract No.: | C-C3085 |
| Country: | Canada |
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| Title: | BONE MARROW MOBILIZATION AS A POTENTIAL THERAPY FOR SPINAL CORD INJURY. |
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| Authors/Affiliations: | 1 Nicole Geremia*; 1 Feng Bao; 1 Lynne Weaver; 1 Greg Dekaban; 1 Arthur Brown;
1 Spinal Cord Injury Team, Robarts Research Institute, University of Western Ontario, Canada
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| Content: | Several studies have demonstrated that intravenous administration of hematopoietc or mesenchymal stem cells improve recovery in animal models of spinal cord injury (SCI). These findings suggest that bone marrow mobilization may be a viable, non-invasive method of achieving stem cell engraftment of the injured spinal cord. We compared the therapeutic effect of three clinically relevant bone marrow mobilizers: Granulocyte-colony stimulating factor (G-CSF), stromal derived factor (SDF-1) analog (CTCE-0214) and a monoclonal antibody (mAb) to the very late antigen 4 (anti-VLA4) in spinal cord-injured mice. In addition to their bone marrow mobilizing effects these mobilizers have other actions that can contribute to recovery following spinal cord injury (SCI). For example, G-CSF has been shown to activate anti-apoptotic pathways, act as a neuroprotective agent, and reduce inflammation in a model of cerebral ischemia. In much the same way, the anti-VLA4 mAb, when administered acutely after SCI in rat, blocks leukocyte infiltration and thereby reduces inflammation and secondary damage.
OBJECTIVES
To compare the therapeutic effects of G-CSF, CTCE-0214 and anti-VLA4 mAb in a mouse model of SCI and to determine if any beneficial effects observed are due to the recruitment of the bone marrow cells into the cord or other mechanisms of action of these reagents.
METHODS
Female C57/BL6 mice underwent an 8g clip compression SCI at the 4th thoracic segment. Following spinal cord injury the mice were treated with G-CSF, CTCE-0214 or anti-VLA4 mAB. Mobilization was confirmed by white blood cell (WBC) counts in intact mice. Inflammation and oxidative damage were assessed at 24hr, 72hr and 1 week after SCI. Leukocyte infiltration of the injured cord was evaluated by immunohistochemistry.
RESULTS
In uninjured mice, we found an increase in WBC counts at 72 hours after treatment with the bone marrow mobilizers. Anti-VLA4 treatment resulted in a 2.8 +/- 0.5 fold increase of WBC counts, while G-CSF and CTCE-0214 resulted in a 1.5 +/- 0.3 and 1.75 +/- 0.7 fold increase, respectively. After SCI there was a significant decrease in markers of inflammation and oxidative damage at 24hr, 72hr and 1 wk with the anti-VLA4 mAb and at 1 week post-injury with the G-CSF treatment. No difference in inflammation or markers of oxidative damage was observed in CTCE-0214-treated animals. Correspondingly, functional recovery was improved by anti-VLA4 and G-CSF treatment but not by CTCE-0214 treatment. We also found a reduced infiltration of bone marrow cells in the chimeric mice with treatment with anti-VLA4 when compared to isotype treatment.
CONCLUSIONS
The use of bone marrow mobilizers can improve functional recovery following SCI, but the results vary depending on the mobilizer used. The beneficial effects observed are likely attributable to mechanisms such as decreased leukocyte infiltration into the cord and reduced secondary damage rather than increased infilitration of bone marrow cells.
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