Abstract
INTRODUCTION:
There are multiple pre-clinical studies showing significant neurological functional benefit of Mesenchymal Stem Cells (MSCs) in cerebral ischemia. MSCs are adult bone marrow derived cells that have a high potential for clinical translation. The optimal route of MSC delivery has not been established. Intra-carotid (IC) delivery via catheters has several attributes attractive for clinical application & may be superior to intravenous (IV) delivery as it circumvents systemic trapping of cells and allows more cells to reach the target lesion. In our previous study using the rat rMCAo model, we found the maximum tolerated dose (MTD) of IC MSCs to be 1 x 10^5 HYPOTHESIS: We tested the hypothesis that the MTD of IC mesenchymal stem cells (MSCs) is more efficacious as compared to IV MSCs and IC control. We further hypothesized that the MTD of IC MSCs given at 24 hours is more efficacious as compared to IC MSCs at 60 minutes. METHODS: 34 female Sprague-Dawley rats underwent 90 minutes reversible middle cerebral artery occlusion (rMCAo). At 60 minutes or 24 hours post rMCAo, rats were assigned to receive: allogeneic IC MSCs at a dose of 1x 10^5 or IC phosphate buffered saline (PBS) 0.5ml or allogeneic intravenous (IV) MSCs 1 x 10^6 & rMCAo with no treatment (sham). Primary outcome measures were blinded neurodeficit score and infarct volume at 4 weeks.
RESULTS:
At 24 hours post rMCAo, there was no significant difference in the neurodeficit score (NDS) amongst the groups. At four weeks post treatment, the IC MSC group showed a significantly lower NDS (7%_3.3) as compared to IV MSCs (10.2%_1.5, p=0.042); In subgroup analysis, IC MSCs given at 60 minutes showed no significant difference compared to other groups, but IC MSC given at 24 hours showed a significantly lower neurodeficit score (5.8 %_2.6) as compared to IC PBS (10.8%_1.2, p=0.003), IV MSCs (10.2 %_1.5, p=0.005) and Sham (10%_ 3.4, p=0.018) (
Fig1
.). The mean infarct volume of the group treated with IC MSCs was significantly lower as compared to IC PBS (18cc%_ 8 vs. 50cc%_17, p=0.043). On infarct topography frequency map comparison, we found a significantly decreased volume of infarction in the cortical regions in IC MSC group as compared to IC PBS group.
CONCLUSIONS:
Treatment with maximum tolerated IC MSC dose of 1 x 10^5 post rMCAO results in superior functional outcome when compared with IV MSC 1 x 10^6, IC PBS and sham rats. Additionally, IC MSC at 24 hours is more efficacious than IC MSC at 60 minutes. There is also a significant decrease in infarct volume in IC MSC treated rats when compared with IC PBS. The IC MSCs may ameliorate injury in the cortex surrounding the core.