Abstract
Exosomes are nano-scale extracellular vesicles secreted by cells and constitute an important part in the cell-cell communication. The main contents of the exosomes include proteins, microRNAs, and lipids. The mechanism and safety of stem cell-derived exosomes have rendered them a promising therapeutic strategy for regenerative medicine. Nevertheless, limited yield has restrained full explication of their functions and clinical applications To address this, various attempts have been made to explore the up- and down-stream manipulations in a bid to increase the production of exosomes. This review has recapitulated factors which may influence the yield of stem cell-derived exosomes, including selection and culture of stem cells, isolation and preservation of the exosomes, and development of artificial exosomes.
Keywords: exosome, stem cell, yield, therapy
Acknowledgements
This work has been sponsored by the National Natural Science Foundation of China (31771065), Sichuan Science and Technology Program (2019JDRC0020), and the “1.3.5 Program for Disciplines of Excellence,” West China Hospital, Sichuan University (ZYJC18002).
Compliance and ethics The author(s) declare that they have no conflict of interest, and all authors have agreed with the publication of this article.
Footnotes
Contributed equally to this work
References
- Alvarez-Viejo M. Mesenchymal stem cells from different sources and their derived exosomes: A pre-clinical perspective. World J Stem Cells. 2020;12:100–109. doi: 10.4252/wjsc.v12.i2.100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ambattu LA, Ramesan S, Dekiwadia C, Hanssen E, Li H, Yeo LY. High frequency acoustic cell stimulation promotes exosome generation regulated by a calcium-dependent mechanism. Commun Biol. 2020;3:553. doi: 10.1038/s42003-020-01277-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- An Y, Lin S, Tan X, Zhu S, Nie F, Zhen Y, Gu L, Zhang C, Wang B, Wei W, et al. Exosomes from adipose-derived stem cells and application to skin wound healing. Cell Prolif. 2021;54:e12993. doi: 10.1111/cpr.12993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Anderson HC. Vesicles associated with calcification in the matrix of epiphyseal cartilage. J Cell Biol. 1969;41:59–72. doi: 10.1083/jcb.41.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Antimisiaris SG, Mourtas S, Marazioti A. Exosomes and exosome-inspired vesicles for targeted drug delivery. Pharmaceutics. 2018;10:218. doi: 10.3390/pharmaceutics10040218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ayala-Mar S, Gallo-Villanueva RC, González-Valdez J. Dielectrophoretic manipulation of exosomes in a multi-section microfluidic device. Mater Today-Proc. 2019;13:332–340. doi: 10.1016/j.matpr.2019.03.162. [DOI] [Google Scholar]
- Bahardoust M, Baghoi-Hosseinabadi Z. Role of adipose-derived mesenchymal stem cells in the regeneration of cardiac tissue and improvement of cardiac function: a narrative review. Biointerface Res Appl Chem. 2021;11:8446–8456. [Google Scholar]
- Bahr MM, Amer MS, Abo-El-Sooud K, Abdallah AN, El-Tookhy OS. Preservation techniques of stem cells extracellular vesicles: a gate for manufacturing of clinical grade therapeutic extracellular vesicles and long-term clinical trials. Int J Vet Sci Med. 2020;8:1–8. doi: 10.1080/23144599.2019.1704992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barile L, Vassalli G. Exosomes: Therapy delivery tools and biomarkers of diseases. Pharmacol Ther. 2017;174:63–78. doi: 10.1016/j.pharmthera.2017.02.020. [DOI] [PubMed] [Google Scholar]
- Batrakova EV, Kim MS. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release. 2015;219:396–405. doi: 10.1016/j.jconrel.2015.07.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Becquart P, Cruel M, Hoc T, Sudre L, Pernelle K, Bizios R, Logeart-Avramoglou D, Petite H, Bensidhoum M. Human mesenchymal stem cell responses to hydrostatic pressure and shear stress. Eur Cell Mater. 2016;31:160–173. doi: 10.22203/eCM.v031a11. [DOI] [PubMed] [Google Scholar]
- Börger V, Bremer M, Ferrer-Tur R, Gockeln L, Stambouli O, Becic A, Giebel B. Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. Int J Mol Sci. 2017;18:1450. doi: 10.3390/ijms18071450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Börger V, Staubach S, Dittrich R, Stambouli O, Giebel B. Scaled isolation of mesenchymal stem/stromal cell-derived extracellular vesicles. Curr Prot Stem Cell Biol. 2020;55:e128. doi: 10.1002/cpsc.128. [DOI] [PubMed] [Google Scholar]
- Bruno S, Chiabotto G, Favaro E, Deregibus MC, Camussi G. Role of extracellular vesicles in stem cell biology. Am J Physiol-Cell Physiol. 2019;317:C303–C313. doi: 10.1152/ajpcell.00129.2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Burrello J, Monticone S, Gai C, Gomez Y, Kholia S, Camussi G. Stem cell-derived extracellular vesicles and immune-modulation. Front Cell Dev Biol. 2016;4:83. doi: 10.3389/fcell.2016.00083. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Busatto S, Vilanilam G, Ticer T, Lin WL, Dickson DW, Shapiro S, Bergese P, Wolfram J. Tangential flow filtration for highly efficient concentration of extracellular vesicles from large volumes of fluid. Cells. 2018;7:273. doi: 10.3390/cells7120273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cardoso RMS, Rodrigues SC, Gomes CF, Duarte FV, Romao M, Leal EC, Freire PC, Neves R, Simões-Correia J. Development of an optimized and scalable method for isolation of umbilical cord blood-derived small extracellular vesicles for future clinical use. Stem Cells Transl Med. 2021;10:910–921. doi: 10.1002/sctm.20-0376. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Charoenviriyakul C, Takahashi Y, Morishita M, Matsumoto A, Nishikawa M, Takakura Y. Cell type-specific and common characteristics of exosomes derived from mouse cell lines: Yield, physicochemical properties, and pharmacokinetics. Eur J Pharm Sci. 2017;96:316–322. doi: 10.1016/j.ejps.2016.10.009. [DOI] [PubMed] [Google Scholar]
- Charoenviriyakul C, Takahashi Y, Nishikawa M, Takakura Y. Preservation of exosomes at room temperature using lyophilization. Int J Pharm. 2018;553:1–7. doi: 10.1016/j.ijpharm.2018.10.032. [DOI] [PubMed] [Google Scholar]
- Chen CY, Rao SS, Ren L, Hu XK, Tan YJ, Hu Y, Luo J, Liu Y W, Yin H, Huang J, et al. Exosomal DMBT1 from human urine-derived stem cells facilitates diabetic wound repair by promoting angiogenesis. Theranostics. 2018;8:1607–1623. doi: 10.7150/thno.22958. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clayton A, Court J, Navabi H, Adams M, Mason MD, Hobot JA, Newman GR, Jasani B. Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. J Immunol Methods. 2001;247:163–174. doi: 10.1016/S0022-1759(00)00321-5. [DOI] [PubMed] [Google Scholar]
- Colao IL, Corteling R, Bracewell D, Wall I. Manufacturing exosomes: a promising therapeutic platform. Trends Mol Med. 2018;24:242–256. doi: 10.1016/j.molmed.2018.01.006. [DOI] [PubMed] [Google Scholar]
- Contreras-Naranjo JC, Wu HJ, Ugaz VM. Microfluidics for exosome isolation and analysis: enabling liquid biopsy for personalized medicine. Lab Chip. 2017;17:3558–3577. doi: 10.1039/C7LC00592J. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Crawford N. The presence of contractile proteins in platelet microparticles isolated from human and animal platelet-free plasma. Br J Haematol. 1971;21:53–69. doi: 10.1111/j.1365-2141.1971.tb03416.x. [DOI] [PubMed] [Google Scholar]
- Damasceno PKF, de Santana TA, Santos GC, Orge ID, Silva DN, Albuquerque JF, Golinelli G, Grisendi G, Pinelli M, Ribeiro Dos Santos R, et al. Genetic engineering as a strategy to improve the therapeutic efficacy of mesenchymal stem/stromal cells in regenerative medicine. Front Cell Dev Biol. 2020;8:737. doi: 10.3389/fcell.2020.00737. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deregibus MC, Figliolini F, D’Antico S, Manzini PM, Pasquino C, De Lena M, Tetta C, Brizzi MF, Camussi G. Charge-based precipitation of extracellular vesicles. Int J Mol Med. 2016;38:1359–1366. doi: 10.3892/ijmm.2016.2759. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F C, Krause DS, Deans RJ, Keating A, Prockop DJ, Horwitz EM. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–317. doi: 10.1080/14653240600855905. [DOI] [PubMed] [Google Scholar]
- Dreux M, Garaigorta U, Boyd B, Décembre E, Chung J, Whitten-Bauer C, Wieland S, Chisari FV. Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host Microbe. 2012;12:558–570. doi: 10.1016/j.chom.2012.08.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Du W, Zhang K, Zhang S, Wang R, Nie Y, Tao H, Han Z, Liang L, Wang D, Liu J, et al. Enhanced proangiogenic potential of mesenchymal stem cell-derived exosomes stimulated by a nitric oxide releasing polymer. Biomaterials. 2017;133:70–81. doi: 10.1016/j.biomaterials.2017.04.030. [DOI] [PubMed] [Google Scholar]
- El-Nesr OH, Yahiya SA, El-Gazayerly ON. Effect of formulation design and freeze-drying on properties of fluconazole multilamellar liposomes. Saudi Pharm J. 2010;18:217–224. doi: 10.1016/j.jsps.2010.07.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Faruqu FN, Zhou S, Sami N, Gheidari F, Lu H, Al-Jamal KT. Three-dimensional culture of dental pulp pluripotent-like stem cells (DPPSCs) enhances Nanog expression and provides a serum-free condition for exosome isolation. FASEB BioAdv. 2020;2:419–433. doi: 10.1096/fba.2020-00025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ferguson SW, Nguyen J. Exosomes as therapeutics: The implications of molecular composition and exosomal heterogeneity. J Control Release. 2016;228:179–190. doi: 10.1016/j.jconrel.2016.02.037. [DOI] [PubMed] [Google Scholar]
- Fernández-Francos S, Eiro N, Costa LA, Escudero-Cernuda S, Fernández-Sánchez ML, Vizoso FJ. Mesenchymal stem cells as a cornerstone in a galaxy of intercellular signals: basis for a new era of medicine. Int J Mol Sci. 2021;22:3576. doi: 10.3390/ijms22073576. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Foroni C, Zarovni N, Bianciardi L, Bernardi S, Triggiani L, Zocco D, Venturella M, Chiesi A, Valcamonico F, Berruti A. When less is more: specific capture and analysis of tumor exosomes in plasma increases the sensitivity of liquid biopsy for comprehensive detection of multiple androgen receptor phenotypes in advanced prostate cancer patients. Biomedicines. 2020;8:131. doi: 10.3390/biomedicines8050131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gámez-Valero A, Monguió-Tortajada M, Carreras-Planella L, Franquesa M, Beyer K, Borràs FE. Size-exclusion chromatography-based isolation minimally alters extracellular vesicles’ characteristics compared to precipitating agents. Sci Rep. 2016;6:33641. doi: 10.1038/srep33641. [DOI] [PMC free article] [PubMed] [Google Scholar]
- García-Manrique P, Gutiérrez G, Blanco-López MC. Fully artificial exosomes: towards new theranostic biomaterials. Trends Biotechnol. 2018;36:10–14. doi: 10.1016/j.tibtech.2017.10.005. [DOI] [PubMed] [Google Scholar]
- Ge Q, Zhou Y, Lu J, Bai Y, Xie X, Lu Z. miRNA in plasma exosome is stable under different storage conditions. Molecules. 2014;19:1568–1575. doi: 10.3390/molecules19021568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Geßner A, Koch B, Klann K, Fuhrmann DC, Farmand S, Schubert R, Münch C, Geiger H, Baer PC. Characterization of extracellular vesicles from preconditioned human adipose-derived stromal/stem cells. Int J Mol Sci. 2021;22:2873. doi: 10.3390/ijms22062873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goh WJ, Zou S, Ong WY, Torta F, Alexandra AF, Schiffelers RM, Storm G, Wang JW, Czarny B, Pastorin G. Bioinspired cell-derived nanovesicles versus exosomes as drug delivery systems: a cost-effective alternative. Sci Rep. 2017;7:14322. doi: 10.1038/s41598-017-14725-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Greening DW, Xu R, Ji H, Tauro BJ, Simpson RJ. A protocol for exosome isolation and characterization: evaluation of ultracentrifugation, density-gradient separation, and immunoaffinity capture methods. Methods Mol Biol. 2015;1295:179–209. doi: 10.1007/978-1-4939-2550-6_15. [DOI] [PubMed] [Google Scholar]
- Guimarães D, Cavaco-Paulo A, Nogueira E. Design of liposomes as drug delivery system for therapeutic applications. Int J Pharm. 2021;601:120571. doi: 10.1016/j.ijpharm.2021.120571. [DOI] [PubMed] [Google Scholar]
- Guo S, Debbi L, Zohar B, Samuel R, Arzi RS, Fried AI, Carmon T, Shevach D, Redenski I, Schlachet I, et al. Stimulating extracellular vesicles production from engineered tissues by mechanical forces. Nano Lett. 2021;21:2497–2504. doi: 10.1021/acs.nanolett.0c04834. [DOI] [PubMed] [Google Scholar]
- Han Z, Peng C, Yi J, Zhang D, Xiang X, Peng X, Su B, Liu B, Shen Y, Qiao L. Highly efficient exosome purification from human plasma by tangential flow filtration based microfluidic chip. Sens Actuat B-Chem. 2021;333:129563. doi: 10.1016/j.snb.2021.129563. [DOI] [Google Scholar]
- Hao ZC, Lu J, Wang SZ, Wu H, Zhang YT, Xu SG. Stem cell-derived exosomes: A promising strategy for fracture healing. Cell Prolif. 2017;50:e12359. doi: 10.1111/cpr.12359. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haraszti RA, Didiot MC, Sapp E, Leszyk J, Shaffer SA, Rockwell HE, Gao F, Narain NR, DiFiglia M, Kiebish MA, et al. High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources. J Extracell Vesicles. 2016;5:32570. doi: 10.3402/jev.v5.32570. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haraszti RA, Miller R, Dubuke ML, Rockwell HE, Coles AH, Sapp E, Didiot MC, Echeverria D, Stoppato M, Sere YY, et al. Serum deprivation of mesenchymal stem cells improves exosome activity and alters lipid and protein composition. Science. 2019;16:230–241. doi: 10.1016/j.isci.2019.05.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haraszti RA, Miller R, Stoppato M, Sere YY, Coles A, Didiot MC, Wollacott R, Sapp E, Dubuke ML, Li X, et al. Exosomes produced from 3D cultures of MSCs by tangential flow filtration show higher yield and improved activity. Mol Ther. 2018;26:2838–2847. doi: 10.1016/j.ymthe.2018.09.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Harrell CR, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells. 2019;8:1605. doi: 10.3390/cells8121605. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heinemann ML, Ilmer M, Silva LP, Hawke DH, Recio A, Vorontsova MA, Alt E, Vykoukal J. Benchtop isolation and characterization of functional exosomes by sequential filtration. J Chromatogr A. 2014;1371:125–135. doi: 10.1016/j.chroma.2014.10.026. [DOI] [PubMed] [Google Scholar]
- Ishiy CSRA, Ormanji MS, Maquigussa E, Ribeiro RS, da Silva Novaes A, Boim MA. Comparison of the effects of mesenchymal stem cells with their extracellular vesicles on the treatment of kidney damage induced by chronic renal artery stenosis. Stem Cells Int. 2020;2020:1–13. doi: 10.1155/2020/8814574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jamshidi E, Babajani A, Soltani P, Niknejad H. Proposed mechanisms of targeting COVID-19 by delivering mesenchymal stem cells and their exosomes to damaged organs. Stem Cell Rev Rep. 2021;17:176–192. doi: 10.1007/s12015-020-10109-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jarmalavičiūtė A, Tunaitis V, Pivoraitė U, Venalis A, Pivoriūnas A. Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis. Cytotherapy. 2015;17:932–939. doi: 10.1016/j.jcyt.2014.07.013. [DOI] [PubMed] [Google Scholar]
- Jeyaram A, Jay SM. Preservation and storage stability of extracellular vesicles for therapeutic applications. AAPS J. 2017;20:1. doi: 10.1208/s12248-017-0160-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ji L, Bao L, Gu Z, Zhou Q, Liang Y, Zheng Y, Xu Y, Zhang X, Feng X. Comparison of immunomodulatory properties of exosomes derived from bone marrow mesenchymal stem cells and dental pulp stem cells. Immunol Res. 2019;67:432–442. doi: 10.1007/s12026-019-09088-6. [DOI] [PubMed] [Google Scholar]
- Ji Y, Han W, Fu X, Li J, Wu Q, Wang Y. Improved small extracellular vesicle secretion of rat adipose-derived stem cells by microgrooved substrates through upregulation of the ESCRT-III-associated protein alix. Adv Healthcare Mater. 2021;10:2100492. doi: 10.1002/adhm.202100492. [DOI] [PubMed] [Google Scholar]
- Jin Y, Chen K, Wang Z, Wang Y, Liu J, Lin L, Shao Y, Gao L, Yin H, Cui C, et al. DNA in serum extracellular vesicles is stable under different storage conditions. BMC Cancer. 2016;16:753. doi: 10.1186/s12885-016-2783-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jo W, Jeong D, Kim J, Cho S, Jang SC, Han C, Kang JY, Gho Y S, Park J. Microfluidic fabrication of cell-derived nanovesicles as endogenous RNA carriers. Lab Chip. 2014;14:1261–1269. doi: 10.1039/C3LC50993A. [DOI] [PubMed] [Google Scholar]
- Jo W, Kim J, Yoon J, Jeong D, Cho S, Jeong H, Yoon YJ, Kim S C, Gho YS, Park J. Large-scale generation of cell-derived nanovesicles. Nanoscale. 2014;6:12056–12064. doi: 10.1039/C4NR02391A. [DOI] [PubMed] [Google Scholar]
- Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:eaau6977. doi: 10.1126/science.aau6977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo S A, Lee JJ, Kalluri R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017;546:498–503. doi: 10.1038/nature22341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kamiya K, Osaki T, Takeuchi S. Formation of nano-sized lipid vesicles with asymmetric lipid components using a pulsed-jet flow method. Sens Actuat B-Chem. 2021;327:128917. doi: 10.1016/j.snb.2020.128917. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kang D, Oh S, Ahn SM, Lee BH, Moon MH. Proteomic analysis of exosomes from human neural stem cells by flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry. J Proteome Res. 2008;7:3475–3480. doi: 10.1021/pr800225z. [DOI] [PubMed] [Google Scholar]
- Katzmann DJ, Babst M, Emr SD. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell. 2001;106:145–155. doi: 10.1016/S0092-8674(01)00434-2. [DOI] [PubMed] [Google Scholar]
- Kim M, Yun HW, Park DY, Choi BH, Min BH. Three-dimensional spheroid culture increases exosome secretion from mesenchymal stem cells. Tissue Eng Regen Med. 2018;15:427–436. doi: 10.1007/s13770-018-0139-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kita S, Shimomura I. Stimulation of exosome biogenesis by adiponectin, a circulating factor secreted from adipocytes. J Biochem. 2020;169:173–179. doi: 10.1093/jb/mvaa105. [DOI] [PubMed] [Google Scholar]
- Koh B, Sulaiman N, Fauzi MB, Law JX, Ng MH, Idrus RBH, Yazid MD. Three dimensional microcarrier system in mesenchymal stem cell culture: a systematic review. Cell Biosci. 2020;10:75. doi: 10.1186/s13578-020-00438-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kornmuller, A., Brown, C.F.C., Yu, C., and Flynn, L.E. (2017). Fabrication of Extracellular Matrix-derived Foams and Microcarriers as Tissue-specific Cell Culture and Delivery Platforms. J Vis Exp, doi: 10.3791/55436. [DOI] [PMC free article] [PubMed]
- Kosaka N, Yoshioka Y, Hagiwara K, Tominaga N, Ochiya T. Functional analysis of exosomal microRNA in cell-cell communication research. Methods Mol Biol. 2013;1024:1–10. doi: 10.1007/978-1-62703-453-1_1. [DOI] [PubMed] [Google Scholar]
- Kowal J, Tkach M, Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014;29:116–125. doi: 10.1016/j.ceb.2014.05.004. [DOI] [PubMed] [Google Scholar]
- Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE, II, Parrott MB, Rosenfeld PJ, Flynn HW, Jr., Goldberg JL. Vision loss after intravitreal injection of autologous “stem cells” for AMD. N Engl J Med. 2017;376:1047–1053. doi: 10.1056/NEJMoa1609583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kyung Kim D, Lee S, Kim M, Jeong Y, Lee S. Exosome-coated silk fibroin 3D-scaffold for inducing osteogenic differentiation of bone marrow derived mesenchymal stem cells. Chem Eng J. 2021;406:127080. doi: 10.1016/j.cej.2020.127080. [DOI] [Google Scholar]
- Lai RC, Arslan F, Lee MM, Sze NSK, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4:214–222. doi: 10.1016/j.scr.2009.12.003. [DOI] [PubMed] [Google Scholar]
- Lane RE, Korbie D, Trau M, Hill MM. Purification protocols for extracellular vesicles. Methods Mol Biol. 2017;1660:111–130. doi: 10.1007/978-1-4939-7253-1_10. [DOI] [PubMed] [Google Scholar]
- Lee BC, Kang I, Yu KR. Therapeutic features and updated clinical trials of mesenchymal stem cell (MSC)-derived exosomes. J Clin Med. 2021;10:711. doi: 10.3390/jcm10040711. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee H, Cha H, Park JH. Derivation of cell-engineered nanovesicles from human induced pluripotent stem cells and their protective effect on the senescence of dermal fibroblasts. Int J Mol Sci. 2020;21:343. doi: 10.3390/ijms21010343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee K, Shao H, Weissleder R, Lee H. Acoustic purification of extracellular microvesicles. ACS Nano. 2015;9:2321–2327. doi: 10.1021/nn506538f. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li J, Lee Y, Johansson HJ, Mäger I, Vader P, Nordin JZ, Wiklander OPB, Lehtiö J, Wood MJA, Andaloussi SE. Serum-free culture alters the quantity and protein composition of neuroblastoma-derived extracellular vesicles. J Extracell Vesicles. 2015;4:26883. doi: 10.3402/jev.v4.26883. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li K, Chang S, Wang Z, Zhao X, Chen D. A novel microemulsion and micelle assembling method to prepare DEC205 monoclonal antibody coupled cationic nanoliposomes for simulating exosomes to target dendritic cells. Int J Pharm. 2015;491:105–112. doi: 10.1016/j.ijpharm.2015.05.068. [DOI] [PubMed] [Google Scholar]
- Li P, Kaslan M, Lee SH, Yao J, Gao Z. Progress in exosome isolation techniques. Theranostics. 2017;7:789–804. doi: 10.7150/thno.18133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li SP, Lin ZX, Jiang XY, Yu XY. Exosomal cargo-loading and synthetic exosome-mimics as potential therapeutic tools. Acta Pharmacol Sin. 2018;39:542–551. doi: 10.1038/aps.2017.178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lin Y, Wu J, Gu W, Huang Y, Tong Z, Huang L, Tan J. Exosome-liposome hybrid nanoparticles deliver CRISPR/Cas9 system in MSCs. Adv Sci. 2018;5:1700611. doi: 10.1002/advs.201700611. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ling Y, Xu W, Yang L, Liang C, Xu B. Improved the biocompatibility of cancellous bone with compound physicochemical decellularization process. Regen Biomater. 2020;7:443–451. doi: 10.1093/rb/rbaa024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu C, Guo J, Tian F, Yang N, Yan F, Ding Y, Wei JY, Hu G, Nie G, Sun J. Field-free isolation of exosomes from extracellular vesicles by microfluidic viscoelastic flows. ACS Nano. 2017;11:6968–6976. doi: 10.1021/acsnano.7b02277. [DOI] [PubMed] [Google Scholar]
- Liu C, Su C. Design strategies and application progress of therapeutic exosomes. Theranostics. 2019;9:1015–1028. doi: 10.7150/thno.30853. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu L, Liu Y, Feng C, Chang J, Fu R, Wu T, Yu F, Wang X, Xia L, Wu C, et al. Lithium-containing biomaterials stimulate bone marrow stromal cell-derived exosomal miR-130a secretion to promote angiogenesis. Biomaterials. 2019;192:523–536. doi: 10.1016/j.biomaterials.2018.11.007. [DOI] [PubMed] [Google Scholar]
- Liu W, Rong Y, Wang J, Zhou Z, Ge X, Ji C, Jiang D, Gong F, Li L, Chen J, et al. Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization. J Neuroinflam. 2020;17:47. doi: 10.1186/s12974-020-1726-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lobb RJ, Becker M, Wen Wen S, Wong CSF, Wiegmans AP, Leimgruber A, Möller A. Optimized exosome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles. 2015;4:27031. doi: 10.3402/jev.v4.27031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lopez-Verrilli MA, Caviedes A, Cabrera A, Sandoval S, Wyneken U, Khoury M. Mesenchymal stem cell-derived exosomes from different sources selectively promote neuritic outgrowth. Neuroscience. 2016;320:129–139. doi: 10.1016/j.neuroscience.2016.01.061. [DOI] [PubMed] [Google Scholar]
- Luo L, Tang J, Nishi K, Yan C, Dinh PU, Cores J, Kudo T, Zhang J, Li TS, Cheng K. Fabrication of synthetic mesenchymal stem cells for the treatment of acute myocardial infarction in mice. Circ Res. 2017;120:1768–1775. doi: 10.1161/CIRCRESAHA.116.310374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maroto R, Zhao Y, Jamaluddin M, Popov VL, Wang H, Kalubowilage M, Zhang Y, Luisi J, Sun H, Culbertson CT, et al. Effects of storage temperature on airway exosome integrity for diagnostic and functional analyses. J Extracell Vesicles. 2017;6:1359478. doi: 10.1080/20013078.2017.1359478. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martinelli C, Gabriele F, Dini E, Carriero F, Bresciani G, Slivinschi B, Dei Giudici M, Zanoletti L, Manai F, Paolillo M, et al. Development of artificial plasma membranes derived nanovesicles suitable for drugs encapsulation. Cells. 2020;9:1626. doi: 10.3390/cells9071626. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Massa M, Croce S, Campanelli R, Abbà C, Lenta E, Valsecchi C, Avanzini MA. Clinical applications of mesenchymal stem/stromal cell derived extracellular vesicles: therapeutic potential of an acellular product. Diagnostics. 2020;10:999. doi: 10.3390/diagnostics10120999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McBride JD, Rodriguez-Menocal L, Guzman W, Candanedo A, Garcia-Contreras M, Badiavas EV. Bone marrow mesenchymal stem cell-derived CD63+ exosomes transport Wnt3a exteriorly and enhance dermal fibroblast proliferation, migration, and angiogenesis in vitro. Stem Cells Dev. 2017;26:1384–1398. doi: 10.1089/scd.2017.0087. [DOI] [PubMed] [Google Scholar]
- Mehryab F, Rabbani S, Shahhosseini S, Shekari F, Fatahi Y, Baharvand H, Haeri A. Exosomes as a next-generation drug delivery system: An update on drug loading approaches, characterization, and clinical application challenges. Acta Biomater. 2020;113:42–62. doi: 10.1016/j.actbio.2020.06.036. [DOI] [PubMed] [Google Scholar]
- Mendt M, Rezvani K, Shpall E. Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplant. 2019;54:789–792. doi: 10.1038/s41409-019-0616-z. [DOI] [PubMed] [Google Scholar]
- Mianehsaz E, Mirzaei HR, Mahjoubin-Tehran M, Rezaee A, Sahebnasagh R, Pourhanifeh MH, Mirzaei H, Hamblin MR. Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis? Stem Cell Res Ther. 2019;10:340. doi: 10.1186/s13287-019-1445-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moleirinho MG, Silva RJS, Carrondo MJT, Alves PM, Peixoto C. Exosome-based therapeutics: Purification using semi-continuous multi-column chromatography. Sep Purif Technol. 2019;224:515–523. doi: 10.1016/j.seppur.2019.04.060. [DOI] [Google Scholar]
- Montecalvo A, Larregina AT, Morelli AE. Methods of analysis of dendritic cell-derived exosome-shuttle microRNA and its horizontal propagation between dendritic cells. Methods Mol Biol. 2013;1024:19–40. doi: 10.1007/978-1-62703-453-1_3. [DOI] [PubMed] [Google Scholar]
- Musante L, Tataruch D, Gu D, Benito-Martin A, Calzaferri G, Aherne S, Holthofer H. A simplified method to recover urinary vesicles for clinical applications and sample banking. Sci Rep. 2014;4:7532. doi: 10.1038/srep07532. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakamura Y, Miyaki S, Ishitobi H, Matsuyama S, Nakasa T, Kamei N, Akimoto T, Higashi Y, Ochi M. Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration. FEBS Lett. 2015;589:1257–1265. doi: 10.1016/j.febslet.2015.03.031. [DOI] [PubMed] [Google Scholar]
- Nordin JZ, Lee Y, Vader P, Mäger I, Johansson HJ, Heusermann W, Wiklander OPB, Hällbrink M, Seow Y, Bultema JJ, et al. Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties. Nanomed-Nanotechnol Biol Med. 2015;11:879–883. doi: 10.1016/j.nano.2015.01.003. [DOI] [PubMed] [Google Scholar]
- Novoseletskaya ES, Grigorieva OA, Efimenko AY, Kalinina NI. Extracellular matrix in the regulation of stem cell differentiation. Biochem Moscow. 2019;84:232–240. doi: 10.1134/S0006297919030052. [DOI] [PubMed] [Google Scholar]
- Obata Y, Kita S, Koyama Y, Fukuda S, Takeda H, Takahashi M, Fujishima Y, Nagao H, Masuda S, Tanaka Y, et al. Adiponectin/T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release. JCI Insight. 2018;3:e99680. doi: 10.1172/jci.insight.99680. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oosthuyzen W, Sime NEL, Ivy JR, Turtle EJ, Street JM, Pound J, Bath LE, Webb DJ, Gregory CD, Bailey MA, et al. Quantification of human urinary exosomes by nanoparticle tracking analysis. J Physiol. 2013;591:5833–5842. doi: 10.1113/jphysiol.2013.264069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30. doi: 10.1038/ncb2000. [DOI] [PubMed] [Google Scholar]
- Park DJ, Yun WS, Kim WC, Park JE, Lee SH, Ha S, Choi JS, Key J, Seo YJ. Improvement of stem cell-derived exosome release efficiency by surface-modified nanoparticles. J Nanobiotechnol. 2020;18:178. doi: 10.1186/s12951-020-00739-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Patel DB, Luthers CR, Lerman MJ, Fisher JP, Jay SM. Enhanced extracellular vesicle production and ethanol-mediated vascularization bioactivity via a 3D-printed scaffold-perfusion bioreactor system. Acta Biomater. 2019;95:236–244. doi: 10.1016/j.actbio.2018.11.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peng KY, Liu YH, Li YW, Yen BL, Yen ML. Extracellular matrix protein laminin enhances mesenchymal stem cell (MSC) paracrine function through αvβ3/CD61 integrin to reduce cardiomyocyte apoptosis. J Cell Mol Med. 2017;21:1572–1583. doi: 10.1111/jcmm.13087. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35:851–858. doi: 10.1002/stem.2575. [DOI] [PubMed] [Google Scholar]
- Piffoux M, Silva AKA, Wilhelm C, Gazeau F, Tareste D. Modification of extracellular vesicles by fusion with liposomes for the design of personalized biogenic drug delivery systems. ACS Nano. 2018;12:6830–6842. doi: 10.1021/acsnano.8b02053. [DOI] [PubMed] [Google Scholar]
- Pusic KM, Pusic AD, Kraig RP. Environmental enrichment stimulates immune cell secretion of exosomes that promote CNS myelination and may regulate inflammation. Cell Mol Neurobiol. 2016;36:313–325. doi: 10.1007/s10571-015-0269-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Qin B, Zhang Q, Hu XM, Mi TY, Yu HY, Liu SS, Zhang B, Tang M, Huang JF, Xiong K. How does temperature play a role in the storage of extracellular vesicles? J Cell Physiol. 2020;235:7663–7680. doi: 10.1002/jcp.29700. [DOI] [PubMed] [Google Scholar]
- Qu Y, Zhang Q, Cai X, Li F, Ma Z, Xu M, Lu L. Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation. J Cell Mol Med. 2017;21:2491–2502. doi: 10.1111/jcmm.13170. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006;20:847–856. doi: 10.1038/sj.leu.2404132. [DOI] [PubMed] [Google Scholar]
- Rekker K, Saare M, Roost AM, Kubo AL, Zarovni N, Chiesi A, Salumets A, Peters M. Comparison of serum exosome isolation methods for microRNA profiling. Clin Biochem. 2014;47:135–138. doi: 10.1016/j.clinbiochem.2013.10.020. [DOI] [PubMed] [Google Scholar]
- Richter, M., Fuhrmann, K., and Fuhrmann, G. (2019). Evaluation of the storage stability of extracellular vesicles. J Vis Exp, doi: 10.3791/59584. [DOI] [PubMed]
- Ruan XF, Ju CW, Shen Y, Liu YT, Kim IM, Yu H, Weintraub N, Wang XL, Tang Y. Suxiao Jiuxin pill promotes exosome secretion from mouse cardiac mesenchymal stem cells in vitro. Acta Pharmacol Sin. 2018;39:569–578. doi: 10.1038/aps.2018.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ryu KJ, Lee JY, Park C, Cho D, Kim SJ. Isolation of small extracellular vesicles from human serum using a combination of ultracentrifugation with polymer-based precipitation. Ann Lab Med. 2020;40:253–258. doi: 10.3343/alm.2020.40.3.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sakai-Kato K, Yoshida K, Takechi-Haraya Y, Izutsu KI. Physicochemical characterization of liposomes that mimic the lipid composition of exosomes for effective intracellular trafficking. Langmuir. 2020;36:12735–12744. doi: 10.1021/acs.langmuir.0c02491. [DOI] [PubMed] [Google Scholar]
- Sarker S, Scholz-Romero K, Perez A, Illanes SE, Mitchell MD, Rice GE, Salomon C. Placenta-derived exosomes continuously increase in maternal circulation over the first trimester of pregnancy. J Transl Med. 2014;12:204. doi: 10.1186/1479-5876-12-204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schiffelers R, Kooijmans S, Vader S, van Dommelen S, Van Solinge S. Exosome mimetics: a novel class of drug delivery systems. Int J Nanomed. 2012;7:1525–1541. doi: 10.2147/IJN.S29661. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sharma A. Role of stem cell derived exosomes in tumor biology. Int J Cancer. 2018;142:1086–1092. doi: 10.1002/ijc.31089. [DOI] [PubMed] [Google Scholar]
- Shi J, Jiang X, Gao S, Zhu Y, Liu J, Gu T, Shi E. Gene-modified exosomes protect the brain against prolonged deep hypothermic circulatory arrest. Ann Thoracic Surg. 2021;111:576–585. doi: 10.1016/j.athoracsur.2020.05.075. [DOI] [PubMed] [Google Scholar]
- Silva AKA, Luciani N, Gazeau F, Aubertin K, Bonneau S, Chauvierre C, Letourneur D, Wilhelm C. Combining magnetic nanoparticles with cell derived microvesicles for drug loading and targeting. Nanomed-Nanotechnol Biol Med. 2015;11:645–655. doi: 10.1016/j.nano.2014.11.009. [DOI] [PubMed] [Google Scholar]
- Sterzenbach U, Putz U, Low LH, Silke J, Tan SS, Howitt J. Engineered exosomes as vehicles for biologically active proteins. Mol Ther. 2017;25:1269–1278. doi: 10.1016/j.ymthe.2017.03.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Strauss K, Goebel C, Runz H, Möbius W, Weiss S, Feussner I, Simons M, Schneider A. Exosome secretion ameliorates lysosomal storage of cholesterol in Niemann-Pick type C disease. J Biol Chem. 2010;285:26279–26288. doi: 10.1074/jbc.M110.134775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sundaram PM, Casadei L, Lopez G, Braggio D, Balakirsky G, Pollock R, Prakash S. Multi-layer micro-nanofluidic device for isolation and capture of extracellular vesicles derived from liposarcoma cell conditioned media. J Microelectromech Syst. 2020;29:776–782. doi: 10.1109/JMEMS.2020.3006786. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Surman M, Drożdż A, Stępień E, Przybylo M. Extracellular vesicles as drug delivery systems—methods of production and potential therapeutic applications. Curr Pharm Des. 2019;25:132–154. doi: 10.2174/1381612825666190306153318. [DOI] [PubMed] [Google Scholar]
- Tang J, Shen D, Caranasos TG, Wang Z, Vandergriff AC, Allen T A, Hensley MT, Dinh PU, Cores J, Li TS, et al. Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome. Nat Commun. 2017;8:13724. doi: 10.1038/ncomms13724. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tang YT, Huang YY, Zheng L, Qin SH, Xu XP, An TX, Xu Y, Wu YS, Hu XM, Ping BH, et al. Comparison of isolation methods of exosomes and exosomal RNA from cell culture medium and serum. Int J Mol Med. 2017;40:834–844. doi: 10.3892/ijmm.2017.3080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tauro BJ, Greening DW, Mathias RA, Ji H, Mathivanan S, Scott AM, Simpson RJ. Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods. 2012;56:293–304. doi: 10.1016/j.ymeth.2012.01.002. [DOI] [PubMed] [Google Scholar]
- Tavassoli H, Alhosseini SN, Tay A, Chan PPY, Weng Oh SK, Warkiani ME. Large-scale production of stem cells utilizing microcarriers: A biomaterials engineering perspective from academic research to commercialized products. Biomaterials. 2018;181:333–346. doi: 10.1016/j.biomaterials.2018.07.016. [DOI] [PubMed] [Google Scholar]
- Tegegn TZ, De Paoli SH, Orecna M, Elhelu OK, Woodle SA, Tarandovskiy ID, Ovanesov MV, Simak J. Characterization of procoagulant extracellular vesicles and platelet membrane disintegration in DMSO-cryopreserved platelets. J Extracell Vesicles. 2016;5:30422. doi: 10.3402/jev.v5.30422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, Zhao Y, Liu H, Fu X, Han W. LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med. 2015;13:308. doi: 10.1186/s12967-015-0642-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Toledano Furman NE, Lupu-Haber Y, Bronshtein T, Kaneti L, Letko N, Weinstein E, Baruch L, Machluf M. Reconstructed stem cell nanoghosts: a natural tumor targeting platform. Nano Lett. 2013;13:3248–3255. doi: 10.1021/nl401376w. [DOI] [PubMed] [Google Scholar]
- Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brügger B, Simons M. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–1247. doi: 10.1126/science.1153124. [DOI] [PubMed] [Google Scholar]
- Tsintou M, Dalamagkas K, Moore TL, Rathi Y, Kubicki M, Rosene DL, Makris N. The use of hydrogel-delivered extracellular vesicles in recovery of motor function in stroke: a testable experimental hypothesis for clinical translation including behavioral and neuroimaging assessment approaches. Neural Regen Res. 2021;16:605. doi: 10.4103/1673-5374.295269. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Turner AEB, Flynn LE. Design and characterization of tissue-specific extracellular matrix-derived microcarriers. Tissue Eng Part C-Methods. 2012;18:186–197. doi: 10.1089/ten.tec.2011.0246. [DOI] [PubMed] [Google Scholar]
- Ueda K, Ishikawa N, Tatsuguchi A, Saichi N, Fujii R, Nakagawa H. Antibody-coupled monolithic silica microtips for highthroughput molecular profiling of circulating exosomes. Sci Rep. 2014;4:6232. doi: 10.1038/srep06232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van der Meel R, Fens MHAM, Vader P, van Solinge WW, Eniola-Adefeso O, Schiffelers RM. Extracellular vesicles as drug delivery systems: lessons from the liposome field. J Control Release. 2014;195:72–85. doi: 10.1016/j.jconrel.2014.07.049. [DOI] [PubMed] [Google Scholar]
- Van Deun J, Roux Q, Deville S, Van Acker T, Rappu P, Miinalainen I, Heino J, Vanhaecke F, De Geest BG, De Wever O, et al. Feasibility of mechanical extrusion to coat nanoparticles with extracellular vesicle membranes. Cells. 2020;9:1797. doi: 10.3390/cells9081797. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vázquez-Ríos AJ, Molina-Crespo Á, Bouzo BL, López-López R, Moreno-Bueno G, de la Fuente M. Exosome-mimetic nanoplatforms for targeted cancer drug delivery. J Nanobiotechnol. 2019;17:85. doi: 10.1186/s12951-019-0517-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang C, Liang C, Wang R, Yao X, Guo P, Yuan W, Liu Y, Song Y, Li Z, Xie X. The fabrication of a highly efficient self-healing hydrogel from natural biopolymers loaded with exosomes for the synergistic promotion of severe wound healing. Biomater Sci. 2019;8:313–324. doi: 10.1039/C9BM01207A. [DOI] [PubMed] [Google Scholar]
- Wang C, Wang M, Xu T, Zhang X, Lin C, Gao W, Xu H, Lei B, Mao C. Engineering bioactive self-healing antibacterial exosomes hydrogel for promoting chronic diabetic wound healing and complete skin regeneration. Theranostics. 2019;9:65–76. doi: 10.7150/thno.29766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang J, Bonacquisti EE, Brown AD, Nguyen J. Boosting the biogenesis and secretion of mesenchymal stem cell-derived exosomes. Cells. 2020;9:660. doi: 10.3390/cells9030660. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Welch JL, Madison MN, Margolick JB, Galvin S, Gupta P, Martínez-Maza O, Dash C, Okeoma CM. Effect of prolonged freezing of semen on exosome recovery and biologic activity. Sci Rep. 2017;7:45034. doi: 10.1038/srep45034. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Witwer KW, Buzás EI, Bemis LT, Bora A, Lässer C, Lötvall J, Nolte-’t Hoen EN, Piper MG, Sivaraman S, Skog J, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013;2:20360. doi: 10.3402/jev.v2i0.20360. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu JY, Li YJ, Hu XB, Huang S, Xiang DX. Preservation of small extracellular vesicles for functional analysis and therapeutic applications: a comparative evaluation of storage conditions. Drug Deliver. 2021;28:162–170. doi: 10.1080/10717544.2020.1869866. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu Z, He D, Li H. Bioglass enhances the production of exosomes and improves their capability of promoting vascularization. Bioactive Mater. 2021;6:823–835. doi: 10.1016/j.bioactmat.2020.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Xu C, Zhao J, Li Q, Hou L, Wang Y, Li S, Jiang F, Zhu Z, Tian L. Exosomes derived from three-dimensional cultured human umbilical cord mesenchymal stem cells ameliorate pulmonary fibrosis in a mouse silicosis model. Stem Cell Res Ther. 2020;11:503. doi: 10.1186/s13287-020-02023-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yan L, Liu G, Wu X. Exosomes derived from umbilical cord mesenchymal stem cells in mechanical environment show improved osteochondral activity via upregulation of LncRNA H19. J Orthop Transl. 2021;26:111–120. doi: 10.1016/j.jot.2020.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yan X, Zhang K, Yang Y, Deng D, Lyu C, Xu H, Liu W, Du Y. Dispersible and dissolvable porous microcarrier tablets enable efficient large-scale human mesenchymal stem cell expansion. Tissue Eng Part C-Methods. 2020;26:263–275. doi: 10.1089/ten.tec.2020.0039. [DOI] [PubMed] [Google Scholar]
- Yáñez-Mó M, Siljander PRM, Andreu Z, Bedina Zavec A, Borràs F E, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066. doi: 10.3402/jev.v4.27066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang D, Zhang W, Zhang H, Zhang F, Chen L, Ma L, Larcher L M, Chen S, Liu N, Zhao Q, et al. Progress, opportunity, and perspective on exosome isolation—efforts for efficient exosome-based theranostics. Theranostics. 2020;10:3684–3707. doi: 10.7150/thno.41580. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang Z, Shi J, Xie J, Wang Y, Sun J, Liu T, Zhao Y, Zhao X, Wang X, Ma Y, et al. Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nat Biomed Eng. 2020;4:69–83. doi: 10.1038/s41551-019-0485-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yao C, Wu W, Tang H, Jia X, Tang J, Ruan X, Li F, Leong DT, Luo D, Yang D. Self-assembly of stem cell membrane-camouflaged nanocomplex for microRNA-mediated repair of myocardial infarction injury. Biomaterials. 2020;257:120256. doi: 10.1016/j.biomaterials.2020.120256. [DOI] [PubMed] [Google Scholar]
- Yin JQ, Zhu J, Ankrum JA. Manufacturing of primed mesenchymal stromal cells for therapy. Nat Biomed Eng. 2019;3:90–104. doi: 10.1038/s41551-018-0325-8. [DOI] [PubMed] [Google Scholar]
- Yoon J, Jo W, Jeong D, Kim J, Jeong H, Park J. Generation of nanovesicles with sliced cellular membrane fragments for exogenous material delivery. Biomaterials. 2015;59:12–20. doi: 10.1016/j.biomaterials.2015.04.028. [DOI] [PubMed] [Google Scholar]
- Yuan Y, Du W, Liu J, Ma W, Zhang L, Du Z, Cai B. Stem cell-derived exosome in cardiovascular diseases: macro roles of micro particles. Front Pharmacol. 2018;9:547. doi: 10.3389/fphar.2018.00547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther. 2019;10:68. doi: 10.1186/s13287-019-1165-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zarovni N, Corrado A, Guazzi P, Zocco D, Lari E, Radano G, Muhhina J, Fondelli C, Gavrilova J, Chiesi A. Integrated isolation and quantitative analysis of exosome shuttled proteins and nucleic acids using immunocapture approaches. Methods. 2015;87:46–58. doi: 10.1016/j.ymeth.2015.05.028. [DOI] [PubMed] [Google Scholar]
- Zeringer, E., Barta, T., Li, M., and Vlassov, A.V. (2015). Strategies for isolation of exosomes. Cold Spring Harb Protoc 2015(4), pdb. top074476. [DOI] [PubMed]
- Zhai M, Zhu Y, Yang M, Mao C. Human mesenchymal stem cell derived exosomes enhance cell-free bone regeneration by altering their miRNAs profiles. Adv Sci. 2020;7:2001334. doi: 10.1002/advs.202001334. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang D, Lee H, Zhu Z, Minhas JK, Jin Y. Enrichment of selective miRNAs in exosomes and delivery of exosomal miRNAs in vitro and in vivo. Am J Physiol-Lung Cell Mol Physiol. 2017;312:L110–L121. doi: 10.1152/ajplung.00423.2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang H, Lyden D. Asymmetric-flow field-flow fractionation technology for exomere and small extracellular vesicle separation and characterization. Nat Protoc. 2019;14:1027–1053. doi: 10.1038/s41596-019-0126-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang J, Nguyen LTH, Hickey R, Walters N, Wang X, Kwak KJ, Lee LJ, Palmer AF, Reátegui E. Immunomagnetic sequential ultrafiltration (iSUF) platform for enrichment and purification of extracellular vesicles from biofluids. Sci Rep. 2021;11:8034. doi: 10.1038/s41598-021-86910-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhao L, Wang Y, Zhang Y. The potential diagnostic and therapeutic applications of exosomes in drug-induced liver injury. Toxicol Lett. 2020;337:68–77. doi: 10.1016/j.toxlet.2020.11.021. [DOI] [PubMed] [Google Scholar]
- Zhou H, Yuen PST, Pisitkun T, Gonzales PA, Yasuda H, Dear JW, Gross P, Knepper MA, Star RA. Collection, storage, preservation, and normalization of human urinary exosomes for biomarker discovery. Kidney Int. 2006;69:1471–1476. doi: 10.1038/sj.ki.5000273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhu LP, Tian T, Wang JY, He JN, Chen T, Pan M, Xu L, Zhang HX, Qiu XT, Li CC, et al. Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics. 2018;8:6163–6177. doi: 10.7150/thno.28021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zonneveld MI, Brisson AR, van Herwijnen MJC, Tan S, van de Lest CHA, Redegeld FA, Garssen J, Wauben MHM, Nolte-’t Hoen ENM. Recovery of extracellular vesicles from human breast milk is influenced by sample collection and vesicle isolation procedures. J Extracell Vesicles. 2014;3:24215. doi: 10.3402/jev.v3.24215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zou W, Lai M, Zhang Y, Zheng L, Xing Z, Li T, Zou Z, Song Q, Zhao X, Xia L, et al. Exosome release is regulated by mTORC1. Adv Sci. 2019;6:1801313. doi: 10.1002/advs.201801313. [DOI] [PMC free article] [PubMed] [Google Scholar]