Exosomal MicroRNAs as Novel Cell-Free Therapeutics in Tissue Engineering and Regenerative Medicine
Abstract
:1. Introduction
2. EV Biogenesis
2.1. Microvesicle Biogenesis
2.2. Exosome Biogenesis
2.2.1. ESCRT-Dependent Pathways
2.2.2. ESCRT-Independent Pathways
3. Exo-miRNA Loading and Sorting in EVs
4. Mechanism for EV Uptake by Recipient Cells and Exosomal miRNA Functions
5. Engineering and Therapeutic Strategies with Exosomal miRs in Regenerative Medicine
5.1. Exo-miR from Mesenchymal Stem Cells (MSCs) in Bone-Associated Regeneration
5.2. Exo-miR from MSCs in Cancer Treatment
5.3. Exo-miR in Alzheimer’s Disease Pathology and Treatment
5.4. Exo-miR in Spinal Cord Injury and Treatment
5.5. Exo-miR from MSCs in Ischemic Diseases
5.6. Exo-miR Detection and EV Biomanufacturing
6. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Proteins | Location | Functions | Ref |
---|---|---|---|
ARF1 | Golgi apparatus and shedding microvesicles | Regulation of matrix degradation by directly acting on the structures associated with invasiveness—invadopodia maturation and the shedding of membrane-derived microvesicles | [10] |
ARF6 | Plasma membrane, cytosol, and endosomal membranes | Regulating the actomyosin-based membrane abscission mechanism to control the shedding of microvesicle in tumor cells | [7] |
Rab22a | Nonclathrin-derived Endosomes, budding microvesicles | Increasing microvesicle shedding in human breast cancer under hypoxic conditions and knockdown of RAB22A impairs breast cancer metastasis | [22] |
RhoA | Membrane and cytosol | Involved in microvesicle biogenesis through regulation of myosin light chain phosphatase. required for microvesicle shedding | [11] |
ARRDC1 | Plasma membrane | ARRDC1-mediated relocalization of TSG101 may alter endosomal trafficking and sorting and signal transduction by receptors subjected to endosomal sorting mechanisms | [23] |
DIAPH3 | Plasma membrane, Microtubules/microvilli | DIAPH3 silencing also promotes shedding of extracellular vesicles (EV) containing bioactive cargo and increases proliferation of recipient tumor cells, and suppresses proliferation of human macrophages and peripheral blood mononuclear cells | [24,25] |
Myosin-1a | Plasma membrane | Enterocyte microvilli containing Myosin-1a are active vesicle-generating organelles | [26] |
Complex | Location | Cargo Sorting | Functions | Ref | |
---|---|---|---|---|---|
ESCRTs-0 | HRS | VHS, FYVE, P(S/T)XP, GAT domain and coiled-coil core, clathrin-binding | Binding to/clustering with ubiquitinated cargo for delivery into MVBs, and recruits clathrin, ubiquitin ligases, and deubiquitinating enzymes, and almost certainly has other functions as well | Clustering of Ub cargo, MVB biogenesis | [31] |
STAM1/2 | VHS, UIM, SH3, GAT domain and coiled-coil core | [32] | |||
ESCRTs-I | TSG101 | UEV, PRD, stalk, headpiece | Binding ubiquitinated cargo, ESCRT-0, ESCRT1, BRO1 and viral proteins | Membrane budding, MVB biogenesis, viral budding, replication and cytolinesis | [33,34] |
HVPS28 | headpiece, Vps28 CTD | ESCRT-0, ESCRT1, BRO1 and viral proteins | [35] | ||
VPS37 | basic helix, stalk, headpiece | Membrane binding | [36] | ||
hMVB12 | stalk, headpiece (“UMA domain”), MAPB | N/A | [37] | ||
ESCRTs-II | EAP20/VPS25 | Winged-helix | Binding ubiquitinated cargo, binding to human ESCRT-I | The essential partner of ESCRT-I in MVB biogenesis and budding formation, membrane budding | [38] |
EAP30/VPS22 | basic helix, Winged-helix | Forming nearly equivalent interactions with the two Vps25 molecules | [39] | ||
EAP45/VPS36 | Winged-helix, GLUE, | Binding PI containing membranes, ubiquitinated cargo and ESCRT-1-i | [40] | ||
ESCRTs-III | CHMP2/VPS2 | MIM1 | Recruits VPS4, initiates ESCRT disassembly | Membrane scission | [41] |
CHMP3/VPS24 | weak MIM1 | Caps Snf7 polymer, recruits VPS2 | [41] | ||
CHMP4/SNF7 | weak MIM2 | Main driver of membrane scission, bind Bro1 | [42] | ||
CHMP6/VPS20 | MIM2 | Binding ESCRT-II and Doa4, acts as nucleator of Snf7 polymer | [41] | ||
VPS4 | SKD1/VPS4 | MIT, AAA | AAA ATPase disassembles ESCRT-III, active function in MVB membrane scission | Vps4 solubilizes ESCRT-III subunits at the cost of ATP hydrolysis. LIP5 binds to Vps4 and promotes its oligomerization, activity, and ESCRT-III binding | [43] |
LIP5 | MIT | Binding vps4 to promote ESCRT-III recycling | [44] |
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Zeng, E.Z.; Chen, I.; Chen, X.; Yuan, X. Exosomal MicroRNAs as Novel Cell-Free Therapeutics in Tissue Engineering and Regenerative Medicine. Biomedicines 2022, 10, 2485. https://doi.org/10.3390/biomedicines10102485
Zeng EZ, Chen I, Chen X, Yuan X. Exosomal MicroRNAs as Novel Cell-Free Therapeutics in Tissue Engineering and Regenerative Medicine. Biomedicines. 2022; 10(10):2485. https://doi.org/10.3390/biomedicines10102485
Chicago/Turabian StyleZeng, Eric Z., Isabelle Chen, Xingchi Chen, and Xuegang Yuan. 2022. "Exosomal MicroRNAs as Novel Cell-Free Therapeutics in Tissue Engineering and Regenerative Medicine" Biomedicines 10, no. 10: 2485. https://doi.org/10.3390/biomedicines10102485