Therapeutic Benefit of Intravenous Administration of Bone Marrow Stromal Cells After Cerebral Ischemia in Rats

Abstract

Background and Purpose-We tested the hypothesis that intravenous infusion of bone marrow derived-marrow stromal cells (MSCs) enter the brain and reduce neurological functional deficits after stroke in rats. Methods-Rats (nϭ32) were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Test groups consisted of MCAO alone (group 1, nϭ6); intravenous infusion of 1ϫ10 6 MSCs at 24 hours after MCAO (group 2, nϭ6); or infusion of 3ϫ106 MSCs (group 3, nϭ7). Rats in groups 1 to 3 were euthanized at 14 days after MCAO. Group 4 consisted of MCAO alone (nϭ6) and group 5, intravenous infusion of 3ϫ10 6 MSCs at 7 days after MCAO (nϭ7). Rats in groups 4 and 5 were euthanized at 35 days after MCAO. For cellular identification, MSCs were prelabeled with bromodeoxyuridine. Behavioral tests (rotarod, adhesive-removal, and modified Neurological Severity Score [NSS]) were performed before and at 1, 7, 14, 21, 28, and 35 days after MCAO. Immunohistochemistry was used to identify MSCs or cells derived from MSCs in brain and other organs. Results-Significant recovery of somatosensory behavior and Neurological Severity Score (PϽ0.05) were found in animals infused with 3ϫ10 6 MSCs at 1 day or 7 days compared with control animals. MSCs survive and are localized to the ipsilateral ischemic hemisphere, and a few cells express protein marker phenotypic neural cells. Conclusions-MSCs delivered to ischemic brain tissue through an intravenous route provide therapeutic benefit after stroke. MSCs may provide a powerful autoplastic therapy for stroke.

Multipotent Mesenchymal Stromal Cells Increase tPA Expression and Concomitantly Decrease PAI-1 Expression in Astrocytes through the Sonic Hedgehog Signaling Pathway after Stroke (in vitro Study)

“…The therapeutic benefits of MSCs on stroke recovery have been shown previously (Chen et al, 2001b;Hardy et al, 2008). Mesenchymal stromal cells promote axonal remodeling in the ischemic boundary zone and enhance functional recovery after stroke through increase of tPA activity (Xin et al, 2010).…”

“…Multipotent mesenchymal stromal cells (MSCs) promote functional recovery after stroke (Chen et al, 2001a;Hardy et al, 2008), in part through tissue plasminogen activator (tPA) activity (Shen et al, 2011). Mesenchymal stromal cells increase tPA activity by concomitantly increasing tPA expression and decreasing plasminogen activator inhibitor 1 (PAI-1) expression in astrocytes in the ischemic boundary zone (Xin et al, 2010).…”

Remyelination of the spinal cord following intravenous delivery of bone marrow cells

“…Systemic injection of bone marrow cells into lethally Xirradiated mice leads to differentiation of neuronal cells in brain (Brazelton et al, 2000;Mezey et al, 2000). Moreover, systemic delivery of bone marrow cells has been shown to enhance functional recovery in rodents following contusive spinal cord injury (Chopp et al, 2000) and middle cerebral artery infarction (Chen et al, 2001). When directly injected into the demyelinated rat spinal cord, isolated marrow cells derived from the mononuclear layer remyelinate these axons (Sasaki et al, 2001).…”

Immune Effects of Mesenchymal Stromal Cells in Experimental Stroke

“…Beneficial effects of MSCs have been demonstrated in rodent models of stroke, where intravenous administration of bone marrow-derived MSCs resulted in smaller infarct volumes and improved functional recovery (Chen et al, 2001;Kurozumi et al, 2005).…”

“…In fact, stroke-induced immunodepression is characterized by autonomic dysfunction and a transient depletion of T-, B-, and natural killer-cell populations, as well as suppression of their effector functions (Prass et al, 2003). Since none of the preclinical or clinical MSC stroke trials has addressed the effects of MSC treatment on strokeinduced immunodepression (Bang et al, 2005;Chen et al, 2001;Honmou et al, 2011;Kurozumi et al, 2005;Lee et al, 2010), we studied the impact of intravenous MSC transplantation on the peripheral immune responses to transient middle cerebral artery occlusion (MCAo) in adult mice.…”