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J Neuroinflammation. 2018 May 3;15(1):135. doi: 10.1186/s12974-018-1153-1.

Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice.

Author information

1
School of Biomedical Engineering and Shanghai Jiao Tong University affiliated sixth people's hospital, Shanghai Jiao Tong University, Shanghai, 200000, China.
2
Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
3
School of Biomedical Engineering and Shanghai Jiao Tong University affiliated sixth people's hospital, Shanghai Jiao Tong University, Shanghai, 200000, China. gyyang@sjtu.edu.cn.
4
Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. gyyang@sjtu.edu.cn.

Abstract

BACKGROUND:

Ischemic 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).

METHODS:

Adult 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.

RESULTS:

We 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).

CONCLUSION:

The 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.

KEYWORDS:

Blood-brain barrier; ICAM-1; Inflammation; Ischemia; Matrixmetallo-proteinase-9; Mesenchymal stem cell

PMID:
29724240
PMCID:
PMC5932816
DOI:
10.1186/s12974-018-1153-1
[Indexed for MEDLINE]
Free PMC Article

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