Mesenchymal stromal cells from rat adipose tissue were transduced with adeno-associated viral (AAV) vector encoding stem cell factor SCF that stimulates proliferation of cardiac c-kit+ cells and improved cardiac function and survival of animals after myocardial infarction. Extracellular vesicles isolated from the medium conditioned by mesenchymal stromal cells by ultracentrifugation were characterized by Western blotting, transmission electron microscopy, nanoparticle tracking analysis, immunostaining, and mass spectrometry analysis. Using proteomic analysis, we identified transgenic SCF in extracellular vesicles released by AAV-modified mesenchymal stromal cells and detected some proteins specific of extracellular vesicles secreted by transduced cells. Extracellular vesicles from AAV-transduced mesenchymal stromal cells could be used for delivery of transgenic proteins as they were readily endocytosed by both cardiosphere-derived cells and cardiac-progenitor cells.
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Dergilev KV, Rubina KA, Sysoeva VJ, Akchurin RS, Tkachuk VA, Parfenova EV. Patent RU No. 2542964. Method for producing progenitor cells of myocardium. Bull. No. 6. Published February 27, 2015.
Armstrong JP, Holme MN, Stevens MM. Re-engineering extracellular vesicles as smart nanoscale therapeutics. ACS Nano. 2017;11(1):69-83.
Cheng L, Zhang K, Wu S, Cui M, Xu T. Focus on mesenchymal stem cell-derived exosomes: opportunities and challenges in cell-free therapy. Stem Cells Int. 2017;2017. ID 6305295. doi: https://doi.org/10.1155/2017/6305295.
Ciardiello C, Cavallini L, Spinelli C, Yang J, Reis-Sobreiro M, de Candia P, Minciacchi VR, Di Vizio D. Focus on extracellular vesicles: new frontiers of cell-to-cell communication in cancer. Int. J. Mol. Sci. 2016;17(2):175. doi: https://doi.org/10.3390/ijms17020175.
Fazel S, Chen L, Weisel RD, Angoulvant D, Seneviratne C, Fazel A, Cheung P, Lam J, Fedak PW, Yau TM, Li RK. Cell transplantation preserves cardiac function after infarction by infarct stabilization: augmentation by stem cell factor. J. Thorac. Cardiovasc. Surg. 2005;130(5):1310.
Gilligan KE, Dwyer RM. Engineering exosomes for cancer therapyn. Int. J. Mol. Sci. 2017;18(6). pii: E1122. doi: https://doi.org/10.3390/ijms18061122.
He JG, Li HR, Han JX, Li BB, Yan D, Li HY, Wang P, Luo Y. GATA-4-expressing mouse bone marrow mesenchymal stem cells improve cardiac function after myocardial infarction via secreted exosomes. Sci. Rep. 2018;8(1):9047. doi: https://doi.org/10.1038/s41598-018-27435-9.
Ishikawa K, Fish K, Aguero J, Yaniz-Galende E, Jeong D, Kho C, Tilemann L, Fish L, Liang L, Eltoukhy AA, Anderson DG, Zsebo K, Costa KD, Hajjar RJ. Stem cell factor gene transfer improves cardiac function after myocardial infarction in swine. Circ. Heart Fail. 2015;8(1):167-174.
Kang K, Ma R, Cai W, Huang W, Paul C, Liang J, Wang Y, Zhao T, Kim HW, Xu M, Millard RW, Wen Z, Wang Y. Exosomes secreted from CXCR4 overexpressing mesenchymal stem cells promote cardioprotection via akt signaling pathway following myocardial infarction. Stem Cells Int. 2015;2015. ID 659890. doi: https://doi.org/10.1155/2015/659890.
Ma J, Zhao Y, Sun L, Sun X, Zhao X, Sun X, Qian H, Xu W, Zhu W. Exosomes derived from akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D. Stem Cells Transl. Med. 2017;6(1):51-59.
Meléndez-Hevia E, De Paz-Lugo P, Cornish-Bowden A, Cárdenas ML. A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis. J. Biosci. 2009;34(6):853-872.
Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D, Thomas P.D. PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucl. Acids Res. 2017;45(D1):D183-D189.
Mingozzi F, High KA. Therapeutic in vivo gene transfer for genetic disease using AAV:progress and challenges. Nat. Rev. Genet. 2011.Vol. 12(5):341-355.
Ohtsuka M, Takano H, Zou Y, Toko H, Akazawa H, Qin Y, Suzuki M, Hasegawa H, Nakaya H, Komuro I. Cytokine therapy prevents left ventricular remodeling and dysfunction after myocardial infarction through neovascularization. FASEB J. 2004.Vol. 18(7):851-853.
Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc. Natl Acad. Sci. USA. 2001;98(18):10,344-10,349.
Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35(4):851-858.
Xiang FL, Lu X, Hammoud L, Zhu P, Chidiac P, Robbins J, Feng Q. Cardiomyocyte-specific overexpression of human stem cell factor improves cardiac function and survival after myocardial infarction in mice. Circulation. 2009;120(12):1065-1074.
Yang Y, Ye Y, Su X, He J, Bai W, He X. MSCs-Derived exosomes and neuroinflammation, neurogenesis and therapy of traumatic brain injury. Front. Cell Neurosci. 2017;11:55. doi: https://doi.org/10.3389/fncel.2017.00055.
Yaniz-Galende E, Chen J, Chemaly E, Liang L, Hulot JS, Mc-Collum L, Arias T, Fuster V, Zsebo KM, Hajjar RJ. Stem cell factor gene transfer promotes cardiac repair after myocardial infarction via in situ recruitment and expansion of c-kit+ cells. Circ. Res. 2012;111(11):1434-1445.
Yu B, Kim HW, Gong M, Wang J, Millard RW, Wang Y, Ashraf M, Xu M. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int. J. Cardiol. 2015;182:349-360.
Zubkova ES, Beloglazova IB, Makarevich PI, Boldyreva MA, Sukhareva OY, Shestakova MV, Dergilev KV, Parfyonova YV, Menshikov MY. Regulation of adipose tissue stem cells angiogenic potential by tumor necrosis factor-alpha. J. Cell. Biochem. 2016;117(1):180-196.
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Translated from Kletochnye Tekhnologii v Biologii i Meditsine, No. 4, pp. 211-219, December, 2018
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Zubkova, E.S., Beloglazova, I.B., Evtushenko, E.G. et al. Application of Adeno-Associated Virus Vectors for Engineering SCF-Containing Extracellular Vesicles of Mesenchymal Stromal Cells. Bull Exp Biol Med 166, 527–534 (2019). https://doi.org/10.1007/s10517-019-04387-2
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DOI: https://doi.org/10.1007/s10517-019-04387-2