Our pre-clinical study demonstrated that the intra-arterial (IA) mesenchymal stem cells (MSCs) delivery reduces infarct volume if delivered at 1 day but not at 1h after a reversible middle cerebral artery occlusion(MCAo)in female rats. The difference in the efficacy of IA MSC delivered at 1h and 1 day after
MCAo emphasis a need to understand a reason, mechanism(s) by which IA MSCs protect the brain and the optimal time window for IA MSC therapy for stroke. Since homing of MSCs at the site of injury require chemokines such as stromal cell derived factor-1 (SDF-1) and MSCs mediated neuroprotection occurs via brain-derived neurotrophic factor (BDNF), we hypothesized that SDF-1 availability is low at 1h after stroke and IA MSCs treatment after MCAo increase brain-derived neurotrophic factor (BDNF) release and tyrosine
kinase receptor sub-type B (TrkB) signaling in the brain. SDF-1 protein level was gradually increased over the period of 24 h after MCAo, suggesting lower levels of SDF-1 at an hour might not be enough for attraction of MSCs after their IA delivery. IA MSCs injection significantly increases in the protein levels of BDNF and phosphorylated TrKB in the penumbra region, as compared to control. To investigate an optimal time window of protection we treated rats with IA MSCs at 1, 2 or 4 days after MCAo. We observed significant reduction in infarct volume and improved neurological score in rats treated at 1 and 2 days respectively, suggesting that IA MSCs is also efficacious at an extended 2 day time window.

Intra-arterial delivery of mesenchymal stem cells activates brain-derived growth factor (BDNF) signaling and improves functional recovery after stroke in female rats