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Cited by 143Barrier Structure and Function StudiesIon Transport and Channel RegulationMesenchymal stem cell research

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Mesenchymal Stem Cells Maintain Blood-Brain Barrier Integrity by Inhibiting Aquaporin-4 Upregulation After Cerebral Ischemia

Tang, Guanghui, Liu, Yanqun, Zhang, Zhijun, Lu, Yifan, Wang, Yang, Huang, Jun, Li, Yaning, Chen, Xiaoyan, Gu, Xiang, Wang, Yongting, Yang, Guo-Yuan·2014·Stem Cells
DOI 10.1002/stem.1808
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Abstract

Rationale: Cerebral ischemia upregulates aquaporin-4 expression, increases blood-brain barrier (BBB) permeability, and induces brain edema. Mesenchymal stem cells (MSCs) can repress inflammatory cytokines and show great potential for ischemic stroke therapy. However, the effect of MSCs regarding the protection of ischemia-induced BBB break down is unknown. Objective: We test whether MSCs therapy protects BBB integrity and explore the molecular mechanisms of aquaporin-4 on BBB integrity. Methods and Results: Two hundred and twenty-eight adult CD1 male mice underwent 90 minutes transient middle cerebral artery occlusion and received 2 × 105 MSCs intracranial transplantation. The neurological severity score was improved and both ischemia-induced brain edema and BBB leakage were reduced in MSC-treated mice. MSCs therapy reduced astrocyte apoptosis and inhibited ischemia-induced aquaporin-4 upregulation. In addition, small-interfering RNA knockdown of aquaporin-4 after cerebral ischemia effectively reduced aquaporin-4 expression, brain edema, BBB leakage, and astrocyte apoptosis. Conditional medium from lipopolysaccharide (LPS)-activated microglia enhanced aquaporin-4 expression, p38 and JNK phosphorylation, and apoptosis of cultured astrocytes. MSC treatment reduced the expression of inflammatory cytokines in LPS-activated microglia, and subsequently reduced aquaporin-4 expression and apoptosis of astrocytes. Knockdown of aquaporin-4 in cultured astrocytes also reduced apoptosis. Treatment with p38 and JNK inhibitors showed that p38, but not the JNK signaling pathway, was responsible for the aquaporin-4 upregulation. Conclusion: MSCs protected BBB integrity by reducing the apoptosis of astrocytes after ischemic attack, which was due to the attenuation of inflammatory response and downregulation of aquaporin-4 expression via p38 signaling pathway. Stem Cells 2014;32:3150–3162

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  • Transplantation of allogeneic mesenchymal stem cells and neural stem cells can stabilize BBB and promote BBB integrity in stroke models, in addition to neuroprotection.

    “For example, transplantation of allogeneic mesenchymal stem cells and neural stem cells, in addition to offering neuroprotection, can stabilize BBB and promote BBB integrity as shown in stroke models (260, 463, 578).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [578]

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Metadata

Authors
Tang, G., Liu, Y., Zhang, Z., Lu, Y., Wang, Y., Huang, J., Li, Y., Chen, X., Gu, X., Wang, Y., & Yang, G.-Y.
Affiliations
Shanghai Jiao Tong University (CN)
Corresponding author
  • Wang, Yongting
  • Yang, Guo-Yuan
ORCID
Venue
Stem Cells
Publisher
Oxford University Press (OUP)
Published
2014-11-26
Volume
32
Issue
12
Pages
3150-3162
ISSN
  • 1066-5099 (ISSN-L)
  • 1549-4918
DOI
10.1002/stem.1808
OpenAlex
W2170263306
Cited by
143
References
1
Citations by year
2026: 2 · 2025: 6 · 2024: 2 · 2023: 10 · 2022: 14 · 2021: 15 · 2020: 20 · 2019: 20 · 2018: 12 · 2017: 15 · 2016: 17 · 2015: 10
FWCI
7.29
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Stem Cells (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (973 Program, #U1232205, 81371305, 2011CB504405)
  • Science and Technology Commission of Shanghai Municipality (13ZR1422600)
  • Shanghai Jiao Tong University
  • National Key Research and Development Program of China (2011CB504405)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
Keywords
mesenchymal stem cells, blood-brain barrier integrity, aquaporin-4, cerebral ischemia, ischemic stroke, cerebral edema, astrocyte apoptosis, microglia, lipopolysaccharide, p38 MAPK signaling, JNK signaling, inflammatory cytokines, middle cerebral artery occlusion
MeSH terms
Animals, Blood-Brain Barrier, Brain Edema, Cerebral Infarction, Brain Ischemia, Disease Models, Animal, Male, Signal Transduction, Up-Regulation, Stroke, Mice, Aquaporin 4, Mesenchymal Stem Cells

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