Background:
Bone marrow mononuclear cells (MNCs) are under investigation as an autologous cell-based therapy for acute ischemic stroke. Both intravenous (IV) and intra-arterial (IA) delivery of MNCs have been brought forward to clinical trials. However, the optimal route of administration for these cells is still unknown and debated. In the present study, we performed a direct comparison of IV vs IA administration of MNCs in a rodent stroke model.
Methods:
Long Evans adult male rats were subjected to middle cerebral artery occlusion (MCAo) for 90 minutes. At 24 hrs after stroke, animals were randomly assigned to either receive saline IV (N=5) or autologous bone marrow derived MNCs 30 million cells/kg via IV (N= 9) injection or an IA (N=8) administration of autologous MNCs 30 million cells/kg. IA infusion was performed over 5 minutes with an infusion pump. Contralateral forepaw use was evaluated by an investigator blinded to treatment groups up to 28 days after stroke. Stroke lesion volume was also measured at 28 days after stroke. Serum cytokines were analyzed from 4 to 28 days after stroke.
Results:
MNCs improved functional recovery and reduced lesion size compared with saline treatment at 28 days after stroke (
Fig
A &
Fig
B, p<0.05). However, there was no significant difference between IV and IA MNC treated groups in either histological or functional outcomes. Serum levels of IL-10 were elevated in animals that received either IV or IA MNCs from 4 to 28 days after stroke, compared with saline controls (Fig C, p<0.05). In addition, serum levels of TNF-α were significantly reduced (Fig D, p<0.05) in both IV and IA MNC treated groups compared to saline controls. We did not observe differences in cytokine levels between IA and IV MNC treated groups for IL-10 and TNF-α. Furthermore, only intravenously administered MNCs led to a significant reduction in serum IL-1β levels, at 4 days after stroke, compared to saline treated controls (p<0.05).
Conclusion:
This is the first study to directly compare delivery routes of bone marrow derived MNCs in a rodent stroke model and assess long term outcomes. MNCs improved neurological recovery and reduced infarction sizes after stroke but we found no differences in outcome based on route of administration. We also found no evidence that either delivery route is superior in modulating the systemic inflammatory response after stroke. These findings have direct clinical implications for the design of clinical trials testing MNCs in patients with ischemic stroke.
Nitric Oxide Facilitates Delivery and Mediates Improved Outcome of Autologous Bone Marrow Mononuclear Cells in a Rodent Stroke Model