Reduced myofibroblast transdifferentiation and fibrotic scarring in ischemic stroke after imatinib treatment
Zeitelhofer, M.; Stefanitsch, C.; Protzmann, J.; Torrente, D.; Adzemovic, M. Z.; Lewandowski, S. A.; Muhl, L.; Eriksson, U.; Nilsson, I.; Su, E. J.; Lawrence, D. A.; Fredriksson, L.
Show abstract
The tyrosine kinase inhibitor imatinib has been reported to improve outcome in patients following ischemic stroke but the exact mechanism remains elusive. Here, utilizing a photothrombotic murine model of middle cerebral artery occlusion (MCAO), we show that imatinib-mediated inhibition of stroke-induced blood-brain barrier (BBB) dysfunction coincided with decreased expression of genes associated with inflammation and fibrosis in the cerebrovasculature. We found that imatinib effectively dampened stroke-induced reactive gliosis and myofibroblast transdifferentiation, whilst having very limited effect on the rest of the glia scar and on peripheral leukocyte infiltration. Further, our data suggest that consolidation of the PDGFR+ portion of the fibrotic scar in imatinib-treated mice contributes to the improvement in functional outcome compared to the vehicle controls, where the PDGFR+ scar is expanding. Comparison with human stroke transcriptome databases revealed significant overlap with imatinib-regulated genes, suggesting imatinib may modulate reactive gliosis and fibrotic scarring also in human stroke.
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