Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment
Abstract
:1. Introduction
2. Mesenchymal Stem Cells (MSCs) and Their Therapeutic Potential for Brain Diseases
2.1. Cell Origins and Therapeutic Functions
2.2. MSCs as Vehicles for Targeted Delivery to the Brain
3. Current Status and Challenges of MSC-Based Therapies
3.1. Current Status of MSC-Based Therapies for Brain Tumors
3.2. Important Issues of MSC-Based Therapies
4. Extracellular Vesicle (EV) Biology
4.1. Classification and Formation
4.2. Biologic Functions at Target Cells
5. Potentials of MSC-EVs as a Cell-Free Platform of Therapeutic Delivery to the Brain
5.1. Advantageous Properties of MSC-EVs for Therapeutic Translation
5.1.1. Intrinsic Ability of Homing to the Brain and Crossing the BBB
5.1.2. Good Biosafety and Bioavailability
5.2. Comparison of EV-Based Platforms with Other Delivery Approaches
5.2.1. Cell-Based Versus Cell-Free Delivery Systems
5.2.2. EVs versus Synthetic Nanoparticles (NPs)
6. Engineering MSC-EVs to Become the Next-Generation Nanocarrier
6.1. Packaging Drugs and Genes into MSC-EVs
6.2. Improving the Functions of MSC-EVs
7. Current Status of MSC-EV Therapeutic Applications in the Brain
7.1. Non-Neoplastic Brain Diseases
7.2. Brain Tumors
7.2.1. Studies Using MSC Secretomes
7.2.2. Studies Using Engineered MSC-EVs
8. Challenges in Applying MSC-EVs to Treat Brain Tumors
8.1. Challenges of EV Production and Characterization
8.1.1. Cell Types of Origin and Cell Senescence
8.1.2. Cell Culture Systems and EV Isolation Methods
8.2. Challenges Related to In Vivo Application of EVs
8.2.1. Pro-Tumor Effects
8.2.2. Pharmacokinetics and Routes of Administration
9. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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MSCs | MSC-EVs | |
---|---|---|
Therapeutic effects | Ineffective engraftment in target tissues including the brain | Better BBB penetration and higher accumulation in brain parenchyma |
Limited options to improve therapeutic effects | More adaptable to a wider range of techniques | |
In vivo application-related issues | Risks of uncontrolled differentiation, immunotoxicity, infection, and embolisms | Better safety profiles |
Technical issues | Limited capacity of ex vivo expansion and large-scale production | Higher yield and easier to scale up |
Complicated processes of final product formation, long-term storage and clinical usage | Less complicated processes | |
Common challenges of both approaches | Poor targeting efficiency due to entrapment in organs after systemic injection Potential of pro-tumor effects Lack of standardized protocols for production and characterization |
Cargo Type | Condition | Study Model | Cargo | Cargo-Loading Method | EV Cell Source | Ref. |
---|---|---|---|---|---|---|
miRNA | Rat brain tumor | in vivo, rat, intracranial xenograft (9L) | miR-146b | Pre-isolation (expression vector transfection using electroporation) | MSCs | [168] |
Glioblastoma | in vitro, human chemoresistant GBM (T98G, U87) | anti-miR-9 | Pre-isolation (synthetic miRNA transfection) | BM-MSCs | [169] | |
Glioblastoma | in vitro, human GBM (U87) and primary GSC | miR-124, miR-145 | Pre-isolation (synthetic miRNA transfection) | BM-MSCs | [170] | |
Glioblastoma | in vitro, human GBM (U87) | miR-124 | Pre-isolation (synthetic miRNA transfection) | human WJ-MSCs | [171] | |
Glioblastoma | in vivo, mouse, intracranial xenograft (primary GSC) | miR-124a | Pre-isolation (lentiviral vector transduction) | human BM-MSCs | [172] | |
Glioblastoma | in vivo, mouse, subcutaneous xenograft (U87) | miR-584 | Pre-isolation (synthetic miRNA transfection) | human MSCs | [173] | |
Glioblastoma | in vivo, mouse, subcutaneous xenograft (U87) | miR-133b | Pre-isolation (synthetic miRNA transfection) | mouse MSCs | [174] | |
Glioblastoma | in vivo, mouse, subcutaneous xenograft (U251) | miR-199a | Pre-isolation (synthetic miRNA transfection) | human MSCs | [175] | |
Glioblastoma | in vivo, mouse, subcutaneous xenograft | miR-375 | Pre-isolation (lentiviral vector transduction) | human MSCs | [176] | |
Glioblastoma | in vivo, mouse, intracranial xenograft (U87) | miR-512-5p | Pre-isolation (lentiviral vector transduction) | human BM-MSCs | [177] | |
Glioblastoma | in vivo, mouse, intracranial xenograft (U87) | miR-29a-3p | Pre-isolation (lentiviral vector transduction) | human BM-MSCs | [178] | |
mRNA | Glioblastoma | in vitro, rat gliosarcoma (C6) | yCD:UPRT | Pre-isolation (lentiviral vector transduction) | human MSCs | [179] |
Glioblastoma | in vitro, human GBM (U118, 8MG-BA) | HSV-TK | Pre-isolation (lentiviral vector transduction) | human MSCs | [180] | |
siRNA | Glioblastoma | in vitro, human GBM (U87, SNB19) | siRNA to the F3-T3 breakpoint | Post-isolation (synthetic siRNA incorporation using electroporation) | human UC-MSCs | [181] |
Protein | Brain metastasis | in vivo, mouse, intracranial xenograft (MDA-MB-231Br) | TRAIL and CXCR4 | Pre-isolation (lentiviral vector transduction) | rat BM-MSCs | [182] |
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Do, A.D.; Kurniawati, I.; Hsieh, C.-L.; Wong, T.-T.; Lin, Y.-L.; Sung, S.-Y. Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment. Int. J. Mol. Sci. 2021, 22, 11187. https://doi.org/10.3390/ijms222011187
Do AD, Kurniawati I, Hsieh C-L, Wong T-T, Lin Y-L, Sung S-Y. Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment. International Journal of Molecular Sciences. 2021; 22(20):11187. https://doi.org/10.3390/ijms222011187
Chicago/Turabian StyleDo, Anh Duy, Ida Kurniawati, Chia-Ling Hsieh, Tai-Tong Wong, Yu-Ling Lin, and Shian-Ying Sung. 2021. "Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment" International Journal of Molecular Sciences 22, no. 20: 11187. https://doi.org/10.3390/ijms222011187