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Mesenchymal stem cells stabilize the blood-brain barrier through regulation of astrocytes.

Park HJ, Shin JY, Kim HN, Oh SH, Song SK, Lee PH - Stem Cell Res Ther (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Brain Research Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea. pphj0105@yuhs.ac.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

MSC treatment reduces BBB permeability in LPS-induced animals. LPS administration into the SN increased EB infiltration and decreased EBA-expressing cells; however, MSC treatment following LPS administration markedly decreased EB infiltration a and increased EBA-immunoreactive cells in the SN b (n = 5). **p <0.01. Scale bar: 20 μm and 100 μm. Number of EBA-positive cells as quantified by stereological analysis c. In addition, MSC treatment significantly decreased the number of P-gp-expressing cells in the SN of LPS-treated animals compared with only LPS-treated animals d, e (n = 5). **p <0.01. Scale bar: 100 μm. EBA endothelial-barrier antigen, LPS lipopolysaccharide, MSC mesenchymal stem cell, p-gp P-glycoprotein
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Fig1: MSC treatment reduces BBB permeability in LPS-induced animals. LPS administration into the SN increased EB infiltration and decreased EBA-expressing cells; however, MSC treatment following LPS administration markedly decreased EB infiltration a and increased EBA-immunoreactive cells in the SN b (n = 5). **p <0.01. Scale bar: 20 μm and 100 μm. Number of EBA-positive cells as quantified by stereological analysis c. In addition, MSC treatment significantly decreased the number of P-gp-expressing cells in the SN of LPS-treated animals compared with only LPS-treated animals d, e (n = 5). **p <0.01. Scale bar: 100 μm. EBA endothelial-barrier antigen, LPS lipopolysaccharide, MSC mesenchymal stem cell, p-gp P-glycoprotein

Mentions: To determine the effects of MSCs on BBB permeability, brain tissue in the SN was stained with EB, a marker for BBB permeability, and antibodies against EBA, a marker of endothelial cells. LPS administration into the SN increased EB infiltration and decreased EBA-positive cells (Fig. 1a, b); however, MSC treatment following LPS administration markedly decreased EB infiltration (Fig. 1a) and increased EBA-positive cells (Fig. 1b). Stereological analysis revealed that MSC treatment significantly increased the number of EBA-positive cells in the SN at 12 hours and 7 days after LPS injection relative to LPS-treated rats (p <0.001; Fig. 1c). In addition, LPS administration caused a marked increase in P-gp-positive cells (Fig. 1d); however, MSC treatment following LPS administration significantly reduced this effect (Fig. 1d). Quantification confirmed that MSC treatment significantly decreased P-gp-positive cells in the SN of LPS-treated animals compared with only LPS-treated animals at 12 hours and 7 days after LPS injection (Fig. 1e; p <0.001).Fig. 1


Mesenchymal stem cells stabilize the blood-brain barrier through regulation of astrocytes.

Park HJ, Shin JY, Kim HN, Oh SH, Song SK, Lee PH - Stem Cell Res Ther (2015)

MSC treatment reduces BBB permeability in LPS-induced animals. LPS administration into the SN increased EB infiltration and decreased EBA-expressing cells; however, MSC treatment following LPS administration markedly decreased EB infiltration a and increased EBA-immunoreactive cells in the SN b (n = 5). **p <0.01. Scale bar: 20 μm and 100 μm. Number of EBA-positive cells as quantified by stereological analysis c. In addition, MSC treatment significantly decreased the number of P-gp-expressing cells in the SN of LPS-treated animals compared with only LPS-treated animals d, e (n = 5). **p <0.01. Scale bar: 100 μm. EBA endothelial-barrier antigen, LPS lipopolysaccharide, MSC mesenchymal stem cell, p-gp P-glycoprotein
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4588687&req=5

Fig1: MSC treatment reduces BBB permeability in LPS-induced animals. LPS administration into the SN increased EB infiltration and decreased EBA-expressing cells; however, MSC treatment following LPS administration markedly decreased EB infiltration a and increased EBA-immunoreactive cells in the SN b (n = 5). **p <0.01. Scale bar: 20 μm and 100 μm. Number of EBA-positive cells as quantified by stereological analysis c. In addition, MSC treatment significantly decreased the number of P-gp-expressing cells in the SN of LPS-treated animals compared with only LPS-treated animals d, e (n = 5). **p <0.01. Scale bar: 100 μm. EBA endothelial-barrier antigen, LPS lipopolysaccharide, MSC mesenchymal stem cell, p-gp P-glycoprotein
Mentions: To determine the effects of MSCs on BBB permeability, brain tissue in the SN was stained with EB, a marker for BBB permeability, and antibodies against EBA, a marker of endothelial cells. LPS administration into the SN increased EB infiltration and decreased EBA-positive cells (Fig. 1a, b); however, MSC treatment following LPS administration markedly decreased EB infiltration (Fig. 1a) and increased EBA-positive cells (Fig. 1b). Stereological analysis revealed that MSC treatment significantly increased the number of EBA-positive cells in the SN at 12 hours and 7 days after LPS injection relative to LPS-treated rats (p <0.001; Fig. 1c). In addition, LPS administration caused a marked increase in P-gp-positive cells (Fig. 1d); however, MSC treatment following LPS administration significantly reduced this effect (Fig. 1d). Quantification confirmed that MSC treatment significantly decreased P-gp-positive cells in the SN of LPS-treated animals compared with only LPS-treated animals at 12 hours and 7 days after LPS injection (Fig. 1e; p <0.001).Fig. 1

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Brain Research Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea. pphj0105@yuhs.ac.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus