Abstract
BackgroundIschemic stroke induced matrixmetallo-proteinase-9 (MMP-9) upregulation, which increased blood-brain barrier permeability. Studies demonstrated that mesenchymal stem cell therapy protected blood-brain barrier disruption from several cerebrovascular diseases. However, the underlying mechanism was largely unknown. We therefore hypothesized that mesenchymal stem cells reduced blood-brain barrier destruction by inhibiting matrixmetallo-proteinase-9 and it was related to intercellular adhesion molecule-1 (ICAM-1).MethodsAdult ICR male mice (n = 118) underwent 90-min middle cerebral artery occlusion and received 2 × 105 mesenchymal stem cell transplantation. Neurobehavioral outcome, infarct volume, and blood-brain barrier permeability were measured after ischemia. The relationship between myeloperoxidase (MPO) activity and ICAM-1 release was further determined.ResultsWe found that intracranial injection of mesenchymal stem cells reduced infarct volume and improved behavioral function in experimental stroke models (p < 0.05). IgG leakage, tight junction protein loss, and inflammatory cytokines IL-1β, IL-6, and TNF-α reduced in mesenchymal stem cell-treated mice compared to the control group following ischemia (p < 0.05). After transplantation, MMP-9 was decreased in protein and activity levels as compared with controls (p < 0.05). Furthermore, myeloperoxidase-positive cells and myeloperoxidase activity were decreased in mesenchymal stem cell-treated mice (p < 0.05).ConclusionThe results showed that mesenchymal stem cell therapy attenuated blood-brain barrier disruption in mice after ischemia. Mesenchymal stem cells attenuated the upward trend of MMP-9 and potentially via downregulating ICAM-1 in endothelial cells. Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) pathway may influence MMP-9 expression of neutrophils and resident cells, and ICAM-1 acted as a key factor in the paracrine actions of mesenchymal stem cell.
Highlights
Ischemic stroke induced matrixmetallo-proteinase-9 (MMP-9) upregulation, which increased bloodbrain barrier permeability
The oxygen-glucose deprivation (OGD) experiment was performed using four groups differentiated as follows: (1) bEND.3 cells (mouse brain microvascular endothelial cells, endothelialpolyoma middle T antigen transformed from cerebral cortex, American Type Culture Collection (ATCC)) alone, (2) bEND.3 cells co-cultured with Mesenchymal stem cells (MSCs), (3) bEND.3 cells cultured with condition medium (CM) of MSCs, and (4) bEND.3 co-cultured with MSCs plus compound C
We demonstrated that ischemia-reperfusion increased MMP-9 expression and this increase was attenuated after MSC transplantation, which was similar to SB-3CT, the inhibitor of MMP-9
Summary
Ischemic stroke induced matrixmetallo-proteinase-9 (MMP-9) upregulation, which increased bloodbrain barrier permeability. Studies demonstrated that mesenchymal stem cell therapy protected blood-brain barrier disruption from several cerebrovascular diseases. We hypothesized that mesenchymal stem cells reduced blood-brain barrier destruction by inhibiting matrixmetallo-proteinase-9 and it was related to intercellular adhesion molecule-1 (ICAM-1). Matrixmetallo-proteinases are a family of zinc and calcium-dependent endopeptidases, which is capable to degrade all components of extracellular matrix (ECM) including laminin, collagen, and fibronectin surrounding the blood-brain barrier (BBB) [3]. MMP-9 is markedly elevated in the late phase of BBB disruption, which occurs at 24–72 h after ischemic stroke [11]. MMP-9 breaks tight junction proteins (e.g., occludin and claudin-5) and basal lamina proteins (e.g., fibronectin, laminin, collagen), resulting in barrier disruption in physiological process. It is noted that inhibition of MMP-9 provided robust protection against the BBB disruption [12], suggesting that MMP-9 was the dominant protease acting at the BBB following ischemic stroke [13]
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