The Smallest Workers in Regenerative Medicine: Stem Cell-Derived Exosomes

Abstract

Extracellular vesicles (EVs) are vesicles secreted by cells into the extracellular space, first discovered in 1967 as platelet dust. In recent years, the idea that EVs can treat various diseases has emerged in studies to understand these vesicles' origin and biological functions. According to their size, biogenesis, content, release pathways and function, EVs have three main subtypes: microvesicle (MV), exosome (EX) and apoptotic body. EVs are found in all body fluids, including urine, plasma, and physiological fluids such as bronchial lavage. In addition, it is secreted by many cell types such as dendritic cells, B cells, T-cells, mast cells, tumour cells, and sperm. This literature article reviewed studies using stem cell-derived EVs in numerous clinical and preclinical studies.

Keywords

• Extracellular Vesicles
• Stem Cell
• Exosome
• Regeneration
• Regenerative Medicine

References

1. Liu W, Ma Z, Li J, Kang X. Mesenchymal stem cell-derived exosomes: therapeutic opportunities and challenges for spinal cord injury. Stem Cell Research & Therapy. 2021 Dec 3;12(1).
2. Biancone L, Bruno S, Deregibus MC, Tetta C, Camussi G. Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrology Dialysis Transplantation. 2012 Aug 1;27(8).
3. Lai RC, Yeo RWY, Tan KH, Lim SK. Exosomes for drug delivery — a novel application for the mesenchymal stem cell. Biotechnology Advances. 2013 Sep;31(5).
4. Gutierrez‐Millan C, Calvo Díaz C, Lanao JM, Colino CI. Advances in Exosomes‐Based Drug Delivery Systems. Macromolecular Bioscience. 2021 Jan 22;21(1).
5. Semedo P, Burgos-Silva M, Donizetti-Oliveira C, Saraiva Camar NO. How do Mesenchymal Stem Cells Repair? In: Stem Cells in Clinic and Research. InTech; 2011.
6. Güneş S, Uysal O, Sevimli T, Sevimli M, Tokhi A, Sarıboyacı A. Kök Hücreler. In: Avci H, editor. Polimerler: Özellikleri ve Uygulamaları. 1st ed. ESOGU; 2021. p. 325–49.
7. Song Y, Kim Y, Ha S, Sheller‐Miller S, Yoo J, Choi C, et al. The emerging role of exosomes as novel therapeutics: Biology, technologies, clinical applications, and the next. American Journal of Reproductive Immunology. 2021 Feb 12;85(2).
8. E Z, G. M, Momen-Heravi F, Hu J, Zhang X, Wu Y, et al. Therapeutic uses of exosomes. Exosomes and Microvesicles. 2013

9. Watanabe Y, Tsuchiya A, Terai S. The development of mesenchymal stem cell therapy in the present, and the perspective of cell-free therapy in the future. Clinical and Molecular Hepatology. 2021 Oct;27(1)
10. Khan M, Nickoloff E, Abramova T, Johnson J, Verma SK, Krishnamurthy P, et al. Embryonic Stem Cell–Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction. Circulation Research. 2015 Oct;117(1).
11. Ranghino A, Bruno S, Bussolati B, Moggio A, Dimuccio V, Tapparo M, et al. The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury. Stem Cell Research & Therapy. 2017 Oct;8(1).
12. McBride JD, Rodriguez-Menocal L, Guzman W, Candanedo A, Garcia-Contreras M, Badiavas E v. Bone Marrow Mesenchymal Stem Cell-Derived CD63 + Exosomes Transport Wnt3a Exteriorly and Enhance Dermal Fibroblast Proliferation, Migration, and Angiogenesis In Vitro. Stem Cells and Development. 2017 Oct;26(19).
13. Zhang S, Chuah SJ, Lai RC, Hui JHP, Lim SK, Toh WS. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2018 Oct;156.
14. Yao J, Zheng J, Cai J, Zeng K, Zhou C, Zhang J, et al. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response. The FASEB Journal. 2019 Oct;33(2).
15. Li X, Liu L, Yang J, Yu Y, Chai J, Wang L, et al. Exosome Derived From Human Umbilical Cord Mesenchymal Stem Cell Mediates MiR-181c Attenuating Burn-induced Excessive Inflammation. EBioMedicine. 2016 Oct;8.
16. Fujii S, Miura Y, Fujishiro A, Shindo T, Shimazu Y, Hirai H, et al. Graft-Versus-Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations. STEM CELLS. 2018 Oct;36(3).
17. Fan Y, Herr F, Vernochet A, Mennesson B, Oberlin E, Durrbach A. Human Fetal Liver Mesenchymal Stem Cell-Derived Exosomes Impair Natural Killer Cell Function. Stem Cells and Development. 2019 Oct;28(1).
18. Kulkarni R, Bajaj M, Ghode S, Jalnapurkar S, Limaye L, Kale VP. Intercellular Transfer of Microvesicles from Young Mesenchymal Stromal Cells Rejuvenates Aged Murine Hematopoietic Stem Cells. STEM CELLS. 2018 Oct;36(3).
19. Liu W, Tang P, Wang J, Ye W, Ge X, Rong Y, et al. Extracellular vesicles derived from melatonin‐preconditioned mesenchymal stem cells containing USP29 repair traumatic spinal cord injury by stabilizing NRF2. Journal of Pineal Research. 2021 Oct;
20. Wang X, Omar O, Vazirisani F, Thomsen P, Ekström K. Mesenchymal stem cell-derived exosomes have altered microRNA profiles and induce osteogenic differentiation depending on the stage of differentiation. PLOS ONE. 2018 Oct;13(2).
21. Cui G, Wu J, Mou F, Xie W, Wang F, Wang Q, et al. Exosomes derived from hypoxia‐preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. The FASEB Journal. 2018 Oct;32(2).
22. Abello J, Nguyen TDT, Marasini R, Aryal S, Weiss ML. Biodistribution of gadolinium- and near infrared-labeled human umbilical cord mesenchymal stromal cell-derived exosomes in tumor bearing mice. Theranostics. 2019;9(8).
23. Wiklander OPB, Nordin JZ, O’Loughlin A, Gustafsson Y, Corso G, Mäger I, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. Journal of Extracellular Vesicles. 2015 Oct;4(1).
24. Patel NA, Moss LD, Lee J-Y, Tajiri N, Acosta S, Hudson C, et al. Long noncoding RNA MALAT1 in exosomes drives regenerative function and modulates inflammation-linked networks following traumatic brain injury. Journal of Neuroinflammation. 2018 Oct;15(1).
25. Kim D, Nishida H, An SY, Shetty AK, Bartosh TJ, Prockop DJ. Chromatographically isolated CD63 + CD81 + extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proceedings of the National Academy of Sciences. 2016 Oct;113(1).
26. Xin H, Katakowski M, Wang F, Qian J-Y, Liu XS, Ali MM, et al. MicroRNA-17–92 Cluster in Exosomes Enhance Neuroplasticity and Functional Recovery After Stroke in Rats. Stroke. 2017 Oct;48(3).
27. de Godoy MA, Saraiva LM, de Carvalho LRP, Vasconcelos-dos-Santos A, Beiral HJ v, Ramos AB, et al. Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-β oligomers. Journal of Biological Chemistry. 2018 Oct;293(6).
28. Liu W, Wang Y, Gong F, Rong Y, Luo Y, Tang P, et al. Exosomes Derived from Bone Mesenchymal Stem Cells Repair Traumatic Spinal Cord Injury by Suppressing the Activation of A1 Neurotoxic Reactive Astrocytes. Journal of Neurotrauma. 2019 Oct;36(3).
29. Ruppert KA, Nguyen TT, Prabhakara KS, Furman NET, Srivastava AK, Harting MT, et al. Human Mesenchymal Stromal Cell-Derived Extracellular Vesicles Modify Microglial Response and Improve Clinical Outcomes in Experimental Spinal Cord Injury. Scientific Reports. 2018 Oct;8(1).
30. Sun G, Li G, Li D, Huang W, Zhang R, Zhang H, et al. hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation. Materials Science and Engineering: C. 2018 Aug;89.
31. Adamiak M, Cheng G, Bobis-Wozowicz S, Zhao L, Kedracka-Krok S, Samanta A, et al. Induced Pluripotent Stem Cell (iPSC)–Derived Extracellular Vesicles Are Safer and More Effective for Cardiac Repair Than iPSCs. Circulation Research. 2018 Oct;122(2).
32. Wang N, Chen C, Yang D, Liao Q, Luo H, Wang X, et al. Mesenchymal stem cells-derived extracellular vesicles, via miR-210, improve infarcted cardiac function by promotion of angiogenesis. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2017 Aug;1863(8).
33. Zhu J, Lu K, Zhang N, Zhao Y, Ma Q, Shen J, et al. Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artificial Cells, Nanomedicine, and Biotechnology. 2017 Oct;
34. Sun X, Shan A, Wei Z, Xu B. Intravenous mesenchymal stem cell-derived exosomes ameliorate myocardial inflammation in the dilated cardiomyopathy. Biochemical and Biophysical Research Communications. 2018 Oct;503(4).
35. Potter DR, Miyazawa BY, Gibb SL, Deng X, Togaratti PP, Croze RH, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate pulmonary vascular permeability and lung injury induced by hemorrhagic shock and trauma. Journal of Trauma and Acute Care Surgery. 2018 Oct;84(2).
36. Tang X-D, Shi L, Monsel A, Li X-Y, Zhu H-L, Zhu Y-G, et al. Mesenchymal Stem Cell Microvesicles Attenuate Acute Lung Injury in Mice Partly Mediated by Ang-1 mRNA. STEM CELLS. 2017 Jul;35(7).
37. Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. Stem Cells and Development. 2020 Oct;29(12).
38. Younis N, Zarif R, Mahfouz R. Inflammatory bowel disease: between genetics and microbiota. Molecular Biology Reports. 2020 Oct;47(4).
39. Cai X, Zhang Z, Yuan J, Ocansey DKW, Tu Q, Zhang X, et al. hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis. Stem Cell Research & Therapy. 2021 Oct;12(1).
40. Barnhoorn MC, Plug L, Jonge ESMM, Molenkamp D, Bos E, Schoonderwoerd MJA, et al. Mesenchymal Stromal Cell–Derived Exosomes Contribute to Epithelial Regeneration in Experimental Inflammatory Bowel Disease. Cellular and Molecular Gastroenterology and Hepatology. 2020;9(4).
41. Haga H, Yan IK, Takahashi K, Matsuda A, Patel T. Extracellular Vesicles from Bone Marrow-Derived Mesenchymal Stem Cells Improve Survival from Lethal Hepatic Failure in Mice. STEM CELLS Translational Medicine. 2017 Oct;6(4).
42. Tamura R, Uemoto S, Tabata Y. Immunosuppressive effect of mesenchymal stem cell-derived exosomes on a concanavalin A-induced liver injury model. Inflammation and Regeneration. 2016 Oct;36(1).
43. Rigo F, Stefano N de, Navarro-Tableros V, David E, Rizza G, Catalano G, et al. Extracellular Vesicles from Human Liver Stem Cells Reduce Injury in an Ex Vivo Normothermic Hypoxic Rat Liver Perfusion Model. Transplantation. 2018 Oct;102(5).
44. Li T, Yan Y, Wang B, Qian H, Zhang X, Shen L, et al. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis. Stem Cells and Development. 2013 Oct;22(6).
45. Yan Y, Jiang W, Tan Y, Zou S, Zhang H, Mao F, et al. hucMSC Exosome-Derived GPX1 Is Required for the Recovery of Hepatic Oxidant Injury. Molecular Therapy. 2017 Oct;25(2).
46. Moisseiev E, Anderson JD, Oltjen S, Goswami M, Zawadzki RJ, Nolta JA, et al. Protective Effect of Intravitreal Administration of Exosomes Derived from Mesenchymal Stem Cells on Retinal Ischemia. Current Eye Research. 2017 Oct;42(10).
47. Shen T, Zheng Q-Q, Shen J, Li Q-S, Song X-H, Luo H-B, et al. Effects of Adipose-derived Mesenchymal Stem Cell Exosomes on Corneal Stromal Fibroblast Viability and Extracellular Matrix Synthesis. Chinese Medical Journal. 2018 Oct;131(6).
48. Yuan X, Li D, Chen X, Han C, Xu L, Huang T, et al. Extracellular vesicles from human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) protect against renal ischemia/reperfusion injury via delivering specificity protein (SP1) and transcriptional activating of sphingosine kinase 1 and inhibiting necroptosis. Cell Death & Disease. 2017 Oct;8(12).
49. Tomasoni S, Longaretti L, Rota C, Morigi M, Conti S, Gotti E, et al. Transfer of Growth Factor Receptor mRNA Via Exosomes Unravels the Regenerative Effect of Mesenchymal Stem Cells. Stem Cells and Development. 2013 Oct;22(5).