TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell–Cell Contact and Extracellular Vesicles
Abstract
:1. Mesenchymal Stem/Stromal Cells (MSCs)
2. Immunoregulatory Properties of BM-MSCs
3. Immunoregulation Mediated by Secreted Factors
4. Immunoregulation Mediated by Cell–Cell Contact
5. Immunoregulation Mediated by Extracellular Vesicles
6. Effect of the Inflammatory Microenvironment on the Immunoregulatory Capacity of MSCs
7. Effects of TNF-α and IFN-γ on the Expression of Immunoregulatory Molecules by MSCs
8. Effects of the Combination of TNF-α and IFN-γ on the Immunoregulatory Capacity of MSCs
9. Important Aspects to Consider for In Vitro Activation Protocols
10. Alterations in Cell Morphology and Proliferation
11. Increased Immunogenicity
12. Increased Expression of Immunoregulatory Molecules
13. Effect of Cytokines on EV-MSC Content
14. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Name Used in the Original Report Cell Source and In Vitro Conditioning Method | Isolation Method | Structures Obtained and Size Range | Study Model | Ref. |
---|---|---|---|---|
Extracellular vesicles Human TA-MSCs IFN-γ (50 ng/mL) for 48 h. | Exosome isolation reagent (Invitrogen). | Microvesicles ≈150–500 nm Mean: 262.4 nm | In vitro: T lymphocyte proliferation and differentiation. | [37] |
Extracellular vesicles Human and murine TA-MSCs Resting MSCs | MVs and Exo preparations: (a) 300× g for 10 min; (b) 2000× g for 10 min; (c) 0.8 µm membrane filtration; (d) 12,500× g for 20 min at room temperature (pure MV isolates); (e) Removing the residual MVs by centrifugation at 20,500× g for 40 min; (f) 0.22 µm membrane filtration; (g) 100,000× g for 70 min (pure Exo isolates). | MVs: Mean: 400–500 nm Exosomes: Mean: 80–100 nm | In vitro: Proliferation and secretion of cytokines by T lymphocytes. | [48] |
Extracellular membrane vesicles Human UCB-MSCs IFN-γ (100 ng/mL) for 24 and 48 h. | (a) 2000× g for 20 min; (b) 100,000× g for 1–2 h. | EV-mix 20–700 nm | In vitro: T lymphocyte proliferation and induction of regulatory T cells. In vivo:Ischemia-reperfusion-induced acute kidney injury rat model. | [85] |
Extracellular Vesicles Human BM-MSCs Resting MSCs | (a) 400× g for 5 min; (b) 2000× g for 20 min; (c)10,000× g for 45 min; (d) 100,000× g for 90 min. | EV-mix 152 ± 23 nm | In vitro: Maturation and secretion of cytokines by CDs. | [87] |
Microvesicles Murine BM-MSCs Resting MSCs | (a) 300× g for 10 min; (b) 1000× g for 20 min; (c) 10,000× g for 30 min; (d) 100,000× g for 2 h. | EV-mix 50–200 nm | In vitro: Proliferation and secretion of cytokines by T lymphocytes. Induction of regulatory T cells. | [90] |
Microvesicles Human WJ-MSCs Resting MSCs | (a) 2000× g for 20 min; (b) 100,000× g for 1 h. | EV-mix 30–500 nm | In vivo: Ischemia-reperfusion-induced acute kidney injury rat model. | [91] |
Microvesicles Human BM-MSCs Resting MSCs | (a) 1500× g for 20 min; (b) 10,000× g for 20 min; (c) 100,000× g for 1 h. | EV-mix 60–160 nm | In vitro: Proliferation and secretion of cytokines by T lymphocytes. Induction of regulatory T cells. | [92] |
Extracellular vesicles Human BM-MSCs TNF-α (20 ng/mL) plus IFN-γ (20 ng/mL) during the night | (a) 0.2-µm membrane filtration; (b) Millipore Lab-scale TFF system equipped with a Biomax 500 kDa Pellicon filter. | Exosomes 75–165 nm | In vitro: Cytokine secretion by activated primary rat splenocytes. | [93] |
Extracellular vesicles Murine TA-MSCsResting MSCs | (a) 2000× g for 20 min; (b) 100,000× g for 2 h. | EV-mix 100–1000 nm | In vitro: T lymphocyte proliferation and induction of regulatory T cells. | [94] |
Microvesicles Human BM-MSCs Resting MSCs | 100,000 g for 1 h at 4°C twice. | EV-mix ≈200 nm | In vitro: Activation of murine mast cells. | [95] |
Microvesicles Human BM-MSCs Resting MSCs | (a) 300× g for 20 min; (b) 100,000× g for 1 h. | EV-mix 50–200 nm | In vitro: Human type II alveolar cells. | [96] |
Microvesicles Human BM-MSCs Hypoxia-induced MSCs | a) 1500× g for 15 min; b) 0.22 μm membrane filtration; c) 170,000× g for 5 h. | Exosomes 50–100 nm | In vitro: Uptake by human umbilical cord endothelial cells. | [97] |
Extracellular vesicles Human BM-MSCs IFN-γ (10 ng/mL) plus TNF-α (15 ng/mL) for 40 to 48 h. | (a) 300× g for 10 min; (b) 2000× g for 30 min; (c) 100,000× g for 90 min. | EV-mix ≈60–400 nm | In vitro: Proliferation and secretion of cytokines by NK, T, and B cells. | [98] |
Exosomes Human BM-MSCs Resting MSCs | (a) 300× g for 10 min; (b) 10,000× g for 20 min; (c) 0.2 µm membrane filtration; (d) 100,000× g for 60 min. | Exosomes 65–100 nm | In vitro: Proliferation and differentiation of T and B lymphocytes. | [99] |
Extracellular vesicles Human BM-MSCs Resting MSCs | (a) 2000× g for 20 min; (b) 100,000× g for 2 h. | EV-mix 61–121 nm | In vitro: Polarization of macrophages. | [100] |
Exosomes MSCs from carcinoma and healthy breast tissue Resting MSCs | Exosome Isolation Kit (Invitrogen). | Exosomes Size not reported | In vitro: Polarization of macrophages. | [101] |
Extracellular vesicles Human BM-MSCs IFN-γ (10 ng/mL) plus TNF-α (15 ng / ml) for 4 h. | (a) 300× g for 10 min; (b) 2000× g for 30 min; (c) 100,000× g for 90 min. | EV-mix ≈25–500 nm | In vitro: Induction of regulatory T cells. In vivo: A xenograft mouse model with steroid-refractory acute graft-versus-host disease. | [102] |
Extracellular vesicles Human UC-MSCs Resting MSCs | (a) 300× g for 10 min; (b) 2000× g for 20 min; (c) 10,000× g for 30 min; (d) 0.2 µm membrane filtration; (e) 100,000× g for 90 min. | Exosomes 105.1–181.1 nm Mean: 139.2 nm | In vivo: Murine model of chronic graft-versus-host disease. Infiltration and activation of macrophages. | [103] |
Extracellular vesicles Human WJ-MSCs Resting MSCs | a) 10,000× g for 20 min; b) 100,000× g for 1 h. | EV-mix 164 ± 10.4 nm | In vivo: Murine model of lung ischemia-reperfusion injury. Cytokine expression levels. | [104] |
Extracellular vesicles Human UC-MSCs Resting MSCs | (a) 2000× g for 20 min; (b) 100,000× g for 60 min. | EV-mix 80–1000 nm | Single-center, randomized, placebo-controlled, phase II/III clinical pilot study. Patients with grade III-IV chronic kidney disease. | [105] |
Small extracellular vesicle Human WJ-MSCs IFN-γ (2.5 ng/mL) Time is not reported | (a) 400× g for 10 min; (b) 2000× g for 30 min; (c) 10,000× g for 1.5 h; (d) 100,000× g for 90 min. | Exosomes 30–150 nm | In vitro: Activation of T lymphocytes. In vivo: Patients with acute graft-versus-host disease. | [106] |
Microvesicles Human BM-MSCs IFN-γ (10 ng/mL) for 72 h | a) 500× g for 15 min; b) 2000× g for 20 min; c) 17,000× g for 60 min. | Microvesicles 130–1000 nm | In vitro: Analysis of changes in the transport of HLA-I and ICAM-1. | [107] |
Exosomes Human TA-MSCs IFN-γ plus TNF-α (10, 20 and 40 ng/mL) for 48 h. | ExoQuick-TC System Biosciences. | Exosomes 115 ± 11.5 nm | In vitro: Polarization of macrophages. | [108] |
Microvesicles Human BM-MSCs IFN-γ (10 ng/mL) for 48 h, 74 h, or 4 days | (a) 300× g for 30 min; (b) 16,500× g for 20 min. | MVs ≈150 nm | In vitro: Induction of regulatory T cells. | [109] |
Exosomes UC-MSCs TGF-β (10 ng/mL) IFN-γ (1000 IU/mL) for 72 h. Alone or combined | (a) 3000× g for 30 min; (b) 0.22 μm membrane filtration;PEG6000 was added; (c) 3000 rpm for 30 min. | Exosomes 141.6 ± 23.3 nm | In vitro: Induction of regulatory T cells. | [110] |
Microvesicles Human BM-MSCs Ischemic brain extract for 24 h. | (a) 2500× g for 10 min; (b) 14,000× g for 45 min at 10 °C. | MVs 150–450 nm | In vitro: Analysis of the content of immunoregulatory molecules. | [111] |
Extracellular vesicles Murine TA-MSC Resting MSCs | MVs and Exo preparations: (a) 300× g for 10 min; (b) 0.8 µm membrane filtration; (c) 12,600× g for 30 min (MVs); (d) 0.22 µm membrane filtration; (g) 100,000× g for 70 min (Exo). | MVs: Mean: 271 nm Exosome: Mean: 90 nm | In vitro: Mouse-derived peritoneal macrophages. | [112] |
Extracellular Vesicles Human UC-MSCs Resting MSCs | (a) 3200× g for 10 min; (b) 10,000× g for 30 min; (c) 100,000× g for 2 h. | EV-mix ≈100–300 nm | In vitro: Activation of CD4 + cells. In vivo: Mouse liver ischemia/reperfusion injury model. | [113] |
Smallextracellular vesicles Human UC-MSCs Resting MSCs | (a) 300× g for 10 min; (b) 2000× g for 10 min; (c) 10,000× g for 30 min; (d) 100,000× g for 70 min. | EV-mix 40–200 nm | In vivo: Rat model of rheumatoid arthritis T lymphocyte proliferation, apoptosis, and differentiation. | [114] |
Extracellular Vesicles Human TA-MSCs Resting MSCs | (a) 0.22 μm membrane filtration; (b) 30,000× g for 20 min; (c) 120,000× g for 3 h. | Exosomes 90–120 nm | In vivo: Mouse model of dextran sodium sulfate-induced colitis. | [115] |
Extracellular vesicles Human PL-MSC Resting MSCs | (a) 500× g for 10 min; (b) 2000× g for 20 min; (c) 5000× g for 30 min; (d) 0.2 µm membrane filtration; (e) 130,000× g for 2 h. | Exosomes 85–125 nm | In vivo: Mouse model of colitis-induced with trinitrobenzene sulfonic acid. | [116] |
Extracellular vesicles Murine BM-MSCs IL-6 (20 ng/mL), TNF-α (25 ng/mL) plus IL-1β (25 ng/mL) for 24 h | (a) 1200 rpm for 6 min; (b) 0.22 mm filter; (c) Ami-Con filters Ultra-15, regenerate cellulose 100,000 NMWL; Merck Millipore); (d) 3200× g at 4 °C for 15 min. | EV-mix ≈30–300 nm | In vivo: Murine model of sodium dextran. Sulfate-induced colitis. Polarization of intestinal macrophages. Regulatory T cell differentiation. | [117] |
Exosomes Human G- MSCs TNF-α (100 ng/mL) for 48 h | (a) 300× g for 10 min; (b) 3000× g for 10 min; (c) 20,000× g for 30 min; (d) 120,000× g for 70 min; (e) Sucrose gradient; (f) 110,000× g for 3 h at 4 °C. | Exosomes Control: 123 ± 3.1 nm TNF-α: 164 ± 7.3 nm | In vitro: Macrophage polarization. In vivo: Ligature-induced periodontitis model in mice. | [118] |
Small extracellular vesicles human TA-MSCs IFN-γ (10 ng/mL) plus TNF-α (15 ng/mL) for 72 h | (a) 800× g for 5 min; (b) 2000× g for 10 min; (c) 0.22 mm pore filters; (d) 110,000× g for 2 h. | EV-mix ≈80–300 nm | In vitro: CD4 T cell proliferation. | [119] |
Extracellular vesicles DP-MSCs IFN-γ (50 ng/mL), TNF-α (10 ng/mL) plus IL-1β (10 ng/mL) for 48 h | (a) 2000× g for 20 min; (b) 10,000× g for 70 min; (c) 0.22 μm membrane filtration; (d) 110,000× g for 120 min. | EV-mix ≈100–350 nm | In vitro: T cell proliferation. In vivo: Delayed-type hypersensitivity mouse model. | [120] |
Extracellular vesicles Human BM-MSCs IFN-γ (25 ng/mL) plus TNF-α (20 ng/mL) for 24 or 48 h | (a) Centrifugation to remove cells and cell debris; (b) 110,000× g for 70 min. | EV-mix ≈100–500 nm | In vitro: Murine primary microglia. In vivo: Triple-transgenic model of Alzheimer’s disease. | [121] |
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López-García, L.; Castro-Manrreza, M.E. TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell–Cell Contact and Extracellular Vesicles. Int. J. Mol. Sci. 2021, 22, 9531. https://doi.org/10.3390/ijms22179531
López-García L, Castro-Manrreza ME. TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell–Cell Contact and Extracellular Vesicles. International Journal of Molecular Sciences. 2021; 22(17):9531. https://doi.org/10.3390/ijms22179531
Chicago/Turabian StyleLópez-García, Lucero, and Marta E. Castro-Manrreza. 2021. "TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell–Cell Contact and Extracellular Vesicles" International Journal of Molecular Sciences 22, no. 17: 9531. https://doi.org/10.3390/ijms22179531