Mesenchymal stem cells stabilize the blood–brain barrier through regulation of astrocytes
Open accessAbstract
Introduction: The blood–brain barrier (BBB) protects the brain against potentially neurotoxic molecules in the circulation, and loss of its integrity may contribute to disease progression in neurodegenerative conditions. Recently, the active role of reactive astrocytes in BBB disruption has become evident in the inflamed brain. In the present study, we investigated whether mesenchymal stem cell (MSC) treatment might modulate reactive astrocytes and thus stabilize BBB integrity through vascular endothelial growth factor A (VEGF-A) signaling in inflammatory conditions. Methods: For the inflamed brain, we injected LPS using a stereotaxic apparatus and MSCs were injected into the tail vein. At 6 hours and 7 days after LPS injection, we analyzed modulatory effects of MSCs on the change of BBB permeability through VEGF-A signaling using immunochemistry and western blot. To determine the effects of MSCs on VEGF-A-related signaling in cellular system, we had used endothelial cells treated with VEGF-A and co-cultured astrocyte and BV 2 cells treated with lipopolysaccharide (LPS) and then these cells were co-cultured with MSCs. Results: In LPS-treated rats, MSCs restored Evans blue infiltration and the number of endothelial-barrier antigen (EBA) and P-glycoprotein (p-gp)-expressing cells, which were significantly altered in LPS-treated animals. Additionally, MSC administration following LPS treatment markedly increased the density of astrocytic filaments around vessels and reversed LPS-induced elevations in VEGF-A levels as well as endothelial nitric oxide synthase (eNOS)-dependent downregulation of tight junction proteins in the endothelium. Consequently, MSC treatment reduced neutrophil infiltration and enhanced survival of midbrain dopaminergic neurons in LPS-treated animals. In cellular system, MSC treatment led to a significant reversion of VEGF-A-induced eNOS and tight junction protein expression in endothelial cells, which led to increased EBA expressing cells. Additionally, MSC treatment significantly attenuated LPS-induced increased expressions of IL-1β in microglia and VEGF-A in astrocytes with an increase in IL-10 levels. Conclusion: The present study indicated that MSCs may stabilize BBB permeability by modulating astrocytic endfeet and VEGF-A signaling, which may be relevant to the treatment of Parkinsonian diseases as a candidate for disease modifying therapeutics.
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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 [463]
The Discussion reports that MSC treatment stabilized BBB permeability and increased dopaminergic-neuron survival in LPS-injected rats. The Animal studies methods identify this as an inflammatory substantia nigra model, not a stroke model; the paper does not report neural stem-cell treatment. It also describes human-donor MSCs injected into rats, rather than allogeneic transplantation. (LLM, conf=0.90)
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Blood-Brain Barrier: From Physiology to Disease and Back
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- Authors
- Park, H. J., Shin, J. Y., Kim, H. N., Oh, S. H., Song, S. K., & Lee, P. H.
- Affiliations
- Yonsei University (KR)
- Corresponding author
- Lee, Phil Hyu
- Venue
- Stem Cell Research & Therapy
- Published
- 2015-09-29
- Volume
- 6
- Issue
- 1
- Pages
- 187-187
- ISSN
- 1757-6512 (ISSN-L)
- PMC
- PMC4588687
- OpenAlex
- W1840306665
- Cited by
- 79
- References
- 30
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 7 · 2023: 8 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 9 · 2018: 8 · 2017: 8 · 2016: 7
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Stem Cell Research & Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI14C0093)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- mesenchymal stem cells, blood-brain barrier, reactive astrocytes, VEGF-A signaling, astrocyte-endothelial interactions, tight junction proteins, endothelial nitric oxide synthase, lipopolysaccharide-induced neuroinflammation, blood-brain barrier permeability, dopaminergic neuron survival, Parkinson's disease, IL-10, microglia, neutrophil infiltration
- MeSH terms
- Animals, Astrocytes, Blood-Brain Barrier, Capillary Permeability, Cells, Cultured, Lipopolysaccharides, Male, Substantia Nigra, Rats, Sprague-Dawley, Microglia, Coculture Techniques, Tight Junctions, Neutrophil Infiltration, Vascular Endothelial Growth Factor A, Nitric Oxide Synthase Type III, Dopaminergic Neurons, Mesenchymal Stem Cells
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