Exosomes: From Potential Culprits to New Therapeutic Promise in the Setting of Cardiac Fibrosis
Abstract
:1. Introduction
1.1. Introduction: Fibrosis
1.1.1. Cardiac Fibroblasts
1.1.2. Molecular Mechanisms of Cardiac Fibrosis
1.1.3. TGFβ Canonical and Non-Canonical Pathways
1.1.4. IL-11 Signaling Pathway
1.1.5. Angiotensin II and Nuclear Factor-κβ
1.1.6. Wnt Pathways
1.2. An Introduction to Extracellular Vesicles
1.2.1. Exosomes Biogenesis
1.2.2. Exosome Uptake Mechanism
1.2.3. Mechanism of ncRNA and Protein Cargo Loading into Exosomes
2. Exosomes for the Treatment of Cardiac Fibrosis
2.1. Potential of ncRNA Targeting for the Treatment of Cardiac Fibrosis
2.1.1. microRNAs
2.1.2. Long Non-Coding RNAs
2.1.3. circRNAs
2.2. Protein Transported by Exosomes
2.3. Stem Cell-Derived Exosomes
2.4. Exosome-Based Therapy: Is It Specific?
2.5. Direct Exosome Engineering for the Treatment of Cardiac Fibrosis
2.6. Indirect Exosome Engineering in the Treatment of Cardiac Fibrosis
3. Conclusions and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Exosomal Cargo | Inflammation | Fibrosis | Other Functions | Reference |
miRNAs | ||||
miR-19a | ND | ND | Improves cell survivability Increases proliferation | [93] |
miR-21-5p | ND | ND | Reduces apoptosis Improved cardiac function Cardioprotective | [92,100] |
miR-22 | ND | ANTI | Reduces apoptosis Reduces infarct size | [94] |
miR-24 | ANTI | ANTI | Preserves myocardial function after MI Inhibits cardiac FB transdifferentiation Promote proliferation of CMs Reduces apoptosis | [108,109] |
miR-27a | PRO | PRO | Inhibits Nrf2 Increases oxidative stress after MI | [108,116] |
miR-28a | PRO | PRO | Inhibits Nrf2 Increases oxidative stress after MI | [108] |
miR-29 | ND | ANTI | Reduces scar formation Reduced infarct zone Reduced MFB proliferation | [113] |
miR-29b | ND | ANTI | Decreases levels of MMP9 | [113] |
miR-34 | PRO | PRO | Reduces cardiac function Induces apoptosis | [108,115] |
miR-130a | ANTI | PRO | Induces angiogenesis | [117,118] |
miR-132 | ANTI | ANTI | Reduces apoptosis Induces angiogenesis | [95,110] |
miR-144 | ND | ND | Reduces infarct size Improves cardiac function | [96] |
miR-146a | PRO | ND | Reduces apoptosis Improves cardiac function | [122,123] |
miR-155 | PRO | ND | Increases cardiac rupture Suppresses cardiac fibroblast proliferation | [124] |
miR-181b | PRO | ANTI | Reduces scar size Cardioprotective Attenuates NF-κB | [97] |
miR-208a | ND | PRO | Induces FB proliferation Induces MFB activation | [119] |
miR-210 | ANTI | ND | Reduces apoptosis Induces angiogenesis Improves cardiac function | [95,121] |
miR-221 | ANTI | ANTI | Reduces apoptosis Reduces autophagy Inhibits MFB activation Reduces infarct size Improves cardiac functions | [111,112] |
miR-294 | ND | ANTI | Reduces CM apoptosis Cardioprotective | [95] |
miR-328 | ND | PRO | n/a | [120] |
miR-378 | ND | ANTI | n/a | [108,114] |
miR-455 | ND | ANTI | Decreases levels of MMP9 | [113] |
lncRNAs | Inflammation | Fibrosis | Other Functions | Reference |
NONMMUT022555 | ND | PRO | Reduces cardiac function Promotes FB proliferation and differentiation | [130] |
SRA1 | ND | PRO | Promotes FB proliferation | [131] |
Chaer | ND | PRO | Causes CM hypertrophy | [125] |
Meg3 | ND | PRO | Regulates MMP-2 production Causes CM hypertrophy Reduces angiogenesis | [125] |
MIAT | ND | PRO | Reduces cardiac function Promotes FB proliferation | [125] |
H19 | PRO | PRO | Increases production of ECM components (collagens, fibronectin) | [125,132] |
MALAT1 | PRO | PRO | Reduces cardiac function Induces FB proliferation Increases production of ECM components (collagens, α-Smooth muscle actin) | [125,133,135] |
Wisper | ND | PRO | Regulates FB gene expression for cell identity, ECM, cell proliferation, and survival | [125,135] |
Mhrt | ND | ANTI | Reduces cardiac hypertrophy | [125,137] |
circRNAs | Inflammation | Fibrosis | Other Functions | Reference |
circRNA_000203 | ND | PRO | Prevents the anti-fibrotic effect of miR-26b-5p Promotes FB proliferation | [140] |
circActa2 | ND | PRO | Increases expression of α-smooth muscle actin | [141,142] |
Proteins | Inflammation | Fibrosis | Other Functions | Reference |
WNT3a | ND | PRO | Causes β-catenin accumulation and translocation | [146] |
WNT5a | ND | PRO | Causes release of IL-6 | [146] |
HSP72 | PRO | ANTI | n/a | [147] |
TNF-α | PRO | PRO | Induces CM apoptosis | [148] |
Clusterin | ND | ANTI | Reduces apoptosis Reduces CM hypertrophy Improves cardiac function | [149] |
Exosome Engineering | Technique | Advantages | Limitations | Reference |
---|---|---|---|---|
Direct engineering | Encapsulation of hydrophobic anti-fibrotic drugs based on sucrose gradients and ultracentrifugation | Improves drug solubility, stability, and bioavailability Protects drug in blood flow Enhances drug effect | Works only for hydrophobic drugs | [158] |
Direct engineering | Encapsulation of drugs through incubation, freeze-thaw cycles, sonication, and extrusion | Allows loading of drugs and molecules inside exosomes Protects drugs from degradation | Causes disruption of exosomal bilayer | [162] |
Direct engineering | Engineering of EV mimetic structures (liposomes) | Enhances targeting of drugs Increased control of structure and contents Can contain drugs and bioactive molecules | Physiochemical instability Low circulation time Can form unwanted degradants | [163,164,165,166,167] |
Indirect engineering | Transfection of a gene encoding exosome-targeting proteins into parent cells | Does not affect morphology of exosomes Enhances selectivity Improves bio-distribution | Currently only CM- targeting peptides are available | [170,171,172,173] |
Indirect engineering | Loading of exogenous proteins through conserved late-domain (L-domain) pathway | Specific mechanism of protein loading into exosomes Functional delivery of proteins to recipient cells | Displays only protein loading | [170] |
Indirect engineering | Protein loading in exosomes based on light sensitive reversible protein–protein interaction module | Specific mechanism of protein loading into exosomes Functional delivery of proteins to recipient cells Controllable mechanism of loading | Displays only protein loading | [174] |
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Tikhomirov, R.; Reilly-O’Donnell, B.; Catapano, F.; Faggian, G.; Gorelik, J.; Martelli, F.; Emanueli, C. Exosomes: From Potential Culprits to New Therapeutic Promise in the Setting of Cardiac Fibrosis. Cells 2020, 9, 592. https://doi.org/10.3390/cells9030592
Tikhomirov R, Reilly-O’Donnell B, Catapano F, Faggian G, Gorelik J, Martelli F, Emanueli C. Exosomes: From Potential Culprits to New Therapeutic Promise in the Setting of Cardiac Fibrosis. Cells. 2020; 9(3):592. https://doi.org/10.3390/cells9030592
Chicago/Turabian StyleTikhomirov, Roman, Benedict Reilly-O’Donnell, Francesco Catapano, Giuseppe Faggian, Julia Gorelik, Fabio Martelli, and Costanza Emanueli. 2020. "Exosomes: From Potential Culprits to New Therapeutic Promise in the Setting of Cardiac Fibrosis" Cells 9, no. 3: 592. https://doi.org/10.3390/cells9030592