Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects
Abstract
:1. Introduction
2. Structure of Blood–Brain Barrier
3. Blood–Brain Barrier Changes Following Ischemia-Induced Brain Injuries
3.1. Tight Junction Disruption and Blood–Brain Barrier Opening
3.2. Morphological Changes and Impaired Interactions of Cellular Components of Blood–Brain Barrier
3.3. Increase of Blood–Brain Barrier Permeability Following Vascular Remodeling
4. Potential Mechanisms of Blood–Brain Barrier Preservation by MSCs Following Ischemia
4.1. MMP Regulation and Attenuating Leukocytes Infiltrations
4.2. Antioxidant and Anti-Inflammatory Mechanism
4.3. Stabilizing Morphology and Crosstalk of Cellular Components Blood–Brain Barrier
4.3.1. Brain Microvascular Endothelial Cells
4.3.2. Astrocytes
4.3.3. Pericytes
Reference | Signaling Pathway | Component of BBB | Molecular Mechanism | Model | Number of Cells and Sources | Route | Time Treatment/Passage |
---|---|---|---|---|---|---|---|
[68] | ICAM/AMPK | MMPs, ICAM-1 | ↓ICAM-1 ↓neutrophil infiltration, ↓MMP-9 | tMCAO | 2 × 105 BMMSC | ICV | 15 min/3 |
[146] | P38 | AQP-4 astrocytes | ↓AQP-4, ↓neuroinflammatory, ↓apoptotic astrocytes | tMCAO | 2 × 105 BMMSC | ICV | 20 min/3 |
[27] | VEGF/eNOS | Astrocytes endfeet | ↑density of astrocytic endfeet, ↑VEGF/eNOS-dependent TJs | LPS | 1 × 106 BMMSC | IV | 4 h/6 |
[115] | IL-6/STAT3 | Astrocytes | ↑IL-6 ↑anti-apoptosis of astrocytes | HIBD | 2 × 105 BMMSC | ICV | 5 days/3–5 |
[35] | VEGF/Flk1 Ang1/Tie2 | Astrocytes BMVECs | ↑Ang1/Tie2 → ↑occludins and VEGF/Flk1 expression ↑vascular maturation | tMCAO | 3 × 106 BMMSC | IV | 24 h/- |
[108] | PRDX4 | BMVECs | ↑PRDX4-mediated antioxidant ↓ ROS | tMCAO | 2 × 106 BMMSC | IV | 24 h/5–10 |
[95] | - | BMVECs | ↓Neutrophil infiltration ↓Endothelial damage | GCI | 1 × 106 ADMSC | IV | Immediately/2 |
[125] | ANXA1-FPR | BMVECs | ↓endothelial resistance | UCO OGD | BMMSC-EVs 2doses ~2 × 107 | IV | 1,4 days/- |
[134] | Mitochondrial TNTs | BMVECs | Transfer mitochondrial to BMVECs via TNTs→↓oxidative stress | tMCAO | 5 × 105 BMMSC | IA | 24 h/3–5 |
[133] | Mitochondrial TNTs | hUVECs | Transfer mitochondrial to hUVECs via TNTs→↓oxidative stress | OGD RO | - | - | 4 h/3–5 |
[142] | TGF-β Smad2/3 | BMVECs | ↑VEGF, ↑Ang-1 | pMCAO | 2 × 106 BMMSC | IV | 3 h/3 |
[36] | VEGF | Gap junctionBMVECs | ↑gap junction-mediated cell-cell interaction ↓glucose, ↓VEGF uptake in ECs | pMCAO | 5 × 105 BMMSC | IV | 24 h/9 |
[37] | NF-kB p65 | Pericytes | ↓NF-kB p65→↓pericyte migration | SCI | BMMSC-EVs 1 dose ~2 × 106 | IV | 30 min/3–5 |
[110] | ER stress | ER Astrocytes | ↓ER stress-induced apoptosis ↓inflammation | tMCAO | 2 × 106 3 doses ADMSC | IV | 0, 12, 24 h/2 |
[94] | - | - | ↓pro-inflammatory, ↓polarize towards M1-phenotype | pMCAO | 4 × 106 cells/kg hAMSC | IV | 24 h/- |
5. Prospective of MSC-Based Strategies
5.1. Mesenchymal Stem Cell Therapy
5.2. MSC-Derived Extracellular Vesicle Therapy
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Do, P.T.; Wu, C.-C.; Chiang, Y.-H.; Hu, C.-J.; Chen, K.-Y. Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects. Int. J. Mol. Sci. 2021, 22, 10045. https://doi.org/10.3390/ijms221810045
Do PT, Wu C-C, Chiang Y-H, Hu C-J, Chen K-Y. Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects. International Journal of Molecular Sciences. 2021; 22(18):10045. https://doi.org/10.3390/ijms221810045
Chicago/Turabian StyleDo, Phuong Thao, Chung-Che Wu, Yung-Hsiao Chiang, Chaur-Jong Hu, and Kai-Yun Chen. 2021. "Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects" International Journal of Molecular Sciences 22, no. 18: 10045. https://doi.org/10.3390/ijms221810045