Intravenous infusion of mesenchymal stem cells promotes functional recovery in a rat model of chronic cerebral infarction

Abstract

OBJECTIVEIntravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow improves behavioral function in rat models of cerebral infarction. Although clinical studies are ongoing, most studies have focused on the acute or subacute phase of stroke. In the present study, MSCs derived from bone marrow of rats were intravenously infused 8 weeks after the induction of a middle cerebral artery occlusion (MCAO) to investigate whether delayed systemic injection of MSCs improves functional outcome in the chronic phase of stroke in rats.METHODSEight weeks after induction of the MCAO, the rats were randomized and intravenously infused with either MSCs or vehicle. Ischemic volume and behavioral performance were examined. Blood-brain barrier (BBB) integrity was assessed by quantifying the leakage of Evans blue into the brain parenchyma after intravenous infusion. Immunohistochemical analysis was also performed to evaluate the stability of the BBB.RESULTSMotor recovery was better in the MSC-treated group than in the vehicle-treated group, with rapid improvement (evident at 1 week post-infusion). In MSC-treated rats, reduced BBB leakage and increased microvasculature/repair and neovascularization were observed.CONCLUSIONSThese results indicate that the systemic infusion of MSCs results in functional improvement, which is associated with structural changes in the chronic phase of cerebral infarction, including in the stabilization of the BBB.

The Effects and Underlying Mechanisms of Cell Therapy on Blood-Brain Barrier Integrity After Ischemic Stroke

“…These effects were potentially mediated via an adenosine monophosphate-activated protein kinase (AMPK)-dependent intercellular adhesion molecule-1 (ICAM-1) downregulation. Recently, Namioka et al provided evidence that intravenous infusion of BMSCs at 8 weeks after MCAO stabilized the BBB, reduced microvascular leakage and improved behavior function, which indicated that BMSCs could exert functional benefits even in the chronic phase of ischemic stroke [ 59 ].…”

Mesenchymal Stem Cells for Neurological Disorders

“…[ 3–6 ] In different animal stroke models, MSC treatment demonstrated increased axonal density and remodeling around the ischemic lesions [ 7–9 ] and was correlated with improved functional recovery. [ 10–15 ] The therapeutic effects of MSC transplantation could be attributed to the secretion of factors that promote axonal growth and neurogenesis. [ 16 ] Recently, Nagahama et al.…”

“…have shown that IV injection of MSCs enhanced cortical connections through the corpus callosum and enhanced the expression of synaptophysin in ipsilateral neurons in a rat model of cerebral infarction. [ 14 ]…”

“…A decrease in BBB permeability in damaged neural tissue was observed following MSC infusion in different stroke models. [ 14,20 ] Recent studies revealed that transplanted MSCs interact with pericytes, astrocytes, and neurons, providing BBB integrity and maintenance. [ 21 ]…”

Cell Therapy of Stroke: Do the Intra-Arterially Transplanted Mesenchymal Stem Cells Cross the Blood–Brain Barrier?

“…Huang et al demonstrated that MSCs induced decline of the tight junction proteins degradation, as well as increased expression of CD31 and pericyte density in the NVU after intravenous administration to rats [ 67 ]. Chung et al [ 68 ] has also shown that systemic administration of MSCs into rats provides a protective effect against hippocampal neuronal death due to reduction of endothelial damage and neutrophil infiltration. Moreover, after IV infusion of MSCs in the model of small vessel disease in stroke-prone spontaneously hypertensive rats, Nakazaki et al [ 69 ] observed restoration of BBB function via activation of both transforming growth factor-β and angiopoietin 1 signaling pathways, leading to remodeling of the microvasculature.…”