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Regeneration of Anti-Hypoxic Myocardial Cells by Transduction of Mesenchymal Stem Cell-Derived Exosomes Containing Tat-Metallothionein Fusion Proteins

  • Qurrat Ul Ain
  • Young Sun Woo
  • Jee Young Chung
  • Yong-Hee Kim
Article
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Abstract

Stem cells secrete many extracellular vesicles such as micro vesicles, exosomes and membrane particles. Exosomes represent characteristics similar to their native cells and exosomes secreted from human mesenchymal stem cells (hMSCs) have demonstrated cardio protective effects. In this study, we examined the synergistic effects of exosomes derived from hMSCs expressing metallothionein (MT), a wellknown therapeutic protein to treat myocardial infarction, for recovery of cell viability in vitro in hypoxic conditions. Tat-metallothionein (Tat-MT) recombinant fusion proteins were prepared by a recombinant method to increase the transduction of metallothionein into exosomes via Tat’s transduction characteristic. Exosomes from hMSCs were transduced with Tat-MT, and characterized by transmission electron microscopy and immunoblotting. Cellular uptake of exosomes and protein was analyzed by confocal microscopy. The cytoprotective effects of exosomes transfected with Tat-MT (Exo/Tat-MT) on cardiomyocytes were evaluated by accessing cell viability. Exo/Tat-MT significantly upregulated cell viability and downregulated apoptosis in cardiomyocytes. The therapeutic potential of exosome-mediated therapeutic protein delivery was demonstrated by strong cell viability (70-80%) under in vitro hypoxic conditions. This study reveals the dual benefits of exosomes derived from hMSCs and highlights a new method of intercellular stem cells mediation for the stem cell-derived treatment of myocardial infarction.

Keywords

exosomes human mesenchymal stem cells tat-metallothionein fusion proteins hypoxia myocardial infarction 

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References

  1. (1).
    D. Lloyd-Jones, R. Adams, M. Carnethon, G. De Simone, T. B. Ferguson, K. Flegal, E. Ford, K. Furie, A. Go, K. Greenlund, N. Haase, S. Hailpern, M. Ho, V. Howard, B. Kissela, S. Kittner, D. Lackland, L. Lisabeth, A. Marelli, M. McDermott, J. Meigs, D. Mozaffarian, G. Nichol, C. O'Donnell, V. Roger, W. Rosamond, R. Sacco, P. Sorlie, R. Stafford, J. Steinberger, T. Thom, S. Wasserthiel-Smoller, N. Wong, J. Wylie-Rosett, and Y. Hong, Circulation, 119, e21 (2009).CrossRefGoogle Scholar
  2. (2).
    M. F. Pittenger and B. J. Martin, Circ. Res., 95, 9 (2004).CrossRefGoogle Scholar
  3. (3).
    K. E. Hatzistergos, H. Quevedo, B. N. Oskouei, Q. Hu, G. S. Feigenbaum, I. S. Margitich, R. Mazhari, A. J. Boyle, J. P. Zambrano, and J. E. Rodriguez, Circ. Res., 107, 913 (2010).CrossRefGoogle Scholar
  4. (4).
    N. Nagaya, K. Kangawa, T. Itoh, T. Iwase, S. Murakami, Y. Miyahara, T. Fujii, M. Uematsu, H. Ohgushi, and M. Yamagishi, Circulation, 112, 1128 (2005).CrossRefGoogle Scholar
  5. (5).
    H. Piao, T. J. Youn, J. S. Kwon, Y. H. Kim, J. W. Bae, D. W. Kim, M. C. Cho, M. M. Lee, and Y. B. Park, Eur. J. Heart Fail., 7, 730 (2005).CrossRefGoogle Scholar
  6. (6).
    H. C. Quevedo, K. E. Hatzistergos, B. N. Oskouei, G. S. Feigenbaum, J. E. Rodriguez, D. Valdes, P. M. Pattany, J. P. Zambrano, Q. Hu, and I. McNiece, Proc. Natl. Acad. Sci., 106, 14022 (2009).CrossRefGoogle Scholar
  7. (7).
    C. Stamm, B. Westphal, H.-D. Kleine, M. Petzsch, C. Kittner, H. Klinge, C. Schümichen, C. A. Nienaber, M. Freund, and G. Steinhoff, Lancet, 361, 45 (2003).CrossRefGoogle Scholar
  8. (8).
    G. P. Meyer, K. C. Wollert, J. Lotz, J. Steffens, P. Lippolt, S. Fichtner, H. Hecker, A. Schaefer, L. Arseniev, and B. Hertenstein, Circulation, 113, 1287 (2006).CrossRefGoogle Scholar
  9. (9).
    B. R. Kwak and F. Mach, Nat. Med., 11, 367 (2005).CrossRefGoogle Scholar
  10. (10).
    J. M. Duran, C. A. Makarewich, T. E. Sharp, T. Starosta, F. Zhu, N. E. Hoffman, Y. Chiba, M. Madesh, R. M. Berretta, and H. Kubo, Circ. Res., 113, 539 (2013).CrossRefGoogle Scholar
  11. (11).
    S. Mureli, C. P. Gans, D. J. Bare, D. L. Geenen, N. M. Kumar, and K. Banach, Am. J. Physiol. Heart Circ. Physiol., 304, H600 (2013).CrossRefGoogle Scholar
  12. (12).
    C. L. Mummery, R. P. Davis, and J. E. Krieger, Sci. Transl. Med., 2, 27ps17 (2010).CrossRefGoogle Scholar
  13. (13).
    A. I. Caplan and J. E. Dennis, J. Cell. Biochem., 98, 1076 (2006).CrossRefGoogle Scholar
  14. (14).
    M. Gnecchi, P. Danieli, and E. Cervio, Vascul. Pharmacol., 57, 48 (2012).CrossRefGoogle Scholar
  15. (15).
    I. Chimenti, R. R. Smith, T.-S. Li, G. Gerstenblith, E. Messina, A. Giacomello, and E. Marbán, Circ. Res., 106, 971 (2010).CrossRefGoogle Scholar
  16. (16).
    M. Gnecchi, H. He, N. Noiseux, O. D. Liang, L. Zhang, F. Morello, H. Mu, L. G. Melo, R. E. Pratt, and J. S. Ingwall, FASEB J., 20, 661 (2006).CrossRefGoogle Scholar
  17. (17).
    T. Deuse, C. Peter, P. W. Fedak, T. Doyle, H. Reichenspurner, W. H. Zimmermann, T. Eschenhagen, W. Stein, J. C. Wu, and R. C. Robbins, Circulation, 120, S247 (2009).CrossRefGoogle Scholar
  18. (18).
    M. Gnecchi, Z. Zhang, A. Ni, and V. J. Dzau, Circ. Res., 103, 1204 (2008).CrossRefGoogle Scholar
  19. (19).
    T. B. Rogers, S. Pati, S. Gaa, D. Riley, A. Y. Khakoo, S. Patel, R. D. Wardlow, C. A. Frederick, G. Hall, and L.-P. He, J. Mol. Cell. Cardiol., 50, 346 (2011).CrossRefGoogle Scholar
  20. (20).
    J. Kota, R. R. Chivukula, K. A. O'Donnell, E. A. Wentzel, C. L. Montgomery, H.-W. Hwang, T.-C. Chang, P. Vivekanandan, M. Torbenson, and K. R. Clark, Cell, 137, 1005 (2009).CrossRefGoogle Scholar
  21. (21).
    L. Alvarez-Erviti, Y. Seow, H. Yin, C. Betts, S. Lakhal, and M. J. Wood, Nat. biotechnol., 29, 341 (2011).CrossRefGoogle Scholar
  22. (22).
    H. Li, S. Zuo, Z. He, Y. Yang, Z. Pasha, Y. Wang, and M. Xu, Am. J. Physiol. Heart Circ. Physiol., 299, H1772 (2010).CrossRefGoogle Scholar
  23. (23).
    L. Timmers, S. K. Lim, F. Arslan, J. S. Armstrong, I. E. Hoefer, P. A. Doevendans, J. J. Piek, R. M. El Oakley, A. Choo, and C. N. Lee, Stem Cell Res., 1, 129 (2008).CrossRefGoogle Scholar
  24. (24).
    R. C. Lai, F. Arslan, M. M. Lee, N. S. K. Sze, A. Choo, T. S. Chen, M. Salto-Tellez, L. Timmers, C. N. Lee, and R. M. El Oakley, Stem. Cell. Res., 4, 214 (2010).CrossRefGoogle Scholar
  25. (25).
    K. S. Lim, M.-J. Cha, J. K. Kim, E. J. Park, J.-W. Chae, T. Rhim, K.-C. Hwang, and Y.-H. Kim, J. Control. Release, 169, 306 (2013).CrossRefGoogle Scholar
  26. (26).
    Y. J. Kang, Y. Li, X. Sun, and X. Sun, Am. J. Physiol. Heart Circ. Physiol, 163, 1579 (2003).Google Scholar
  27. (27).
    Y. J. Kang, G. Li, and J. T. Saari, Am. J. Physiol. Heart Circ. Physiol, 276, H993 (1999).CrossRefGoogle Scholar
  28. (28).
    R. Watson, H. P. Redmond, J. H. Wang, and D. Bouchier-Hayes, J. Leukoc. Biol., 60, 625 (1996).CrossRefGoogle Scholar
  29. (29).
    J. Rehman, D. Traktuev, J. Li, S. Merfeld-Clauss, C. J. Temm-Grove, J. E. Bovenkerk, C. L. Pell, B. H. Johnstone, R. V. Considine, and K. L. March, Circulation, 109, 1292 (2004).CrossRefGoogle Scholar
  30. (30).
    M. F. Pittenger, A. M. Mackay, S. C. Beck, R. K. Jaiswal, R. Douglas, J. D. Mosca, M. A. Moorman, D. W. Simonetti, S. Craig, and D. R. Marshak, Science, 284, 143 (1999).CrossRefGoogle Scholar
  31. (31).
    Y. L. Tang, Q. Zhao, Y. C. Zhang, L. Cheng, M. Liu, J. Shi, Y. Z. Yang, C. Pan, J. Ge, M. I. Phillips, Regul. Pept., 117, 3 (2004).CrossRefGoogle Scholar
  32. (32).
    X. Zhuang, X. Xiang, W. Grizzle, D. Sun, S. Zhang, R. C. Axtell, S. Ju, J. Mu, L. Zhang, L. Steinman, Mol. Ther., 19, 1769 (2011).CrossRefGoogle Scholar
  33. (33).
    Y. Zhang, M. Chopp, Y. Meng, M. Katakowski, H. Xin, A. Mahmood, and Y. Xiong, J. Neurosurg., 122, 856 (2015).CrossRefGoogle Scholar
  34. (34).
    X.-C. Jiang and J.-Q. Gao, Int. J. Pharm., 521, 167 (2017).CrossRefGoogle Scholar
  35. (35).
    L. Kumar, S. Verma, B. Vaidya, and V. Gupta, Curr. Pharm. Des., 21, 4556 (2015).CrossRefGoogle Scholar
  36. (36).
    L. Huang, W. Ma, Y. Ma, D. Feng, H. Chen, and B. Cai, Int. J. Biol. Sci., 11, 238 (2015).CrossRefGoogle Scholar
  37. (37).
    R. William, G. Watson, H. P. Redmond, J. H. Wang, and D. Bouchier-Hayes, J. Leukoc. Biol., 60, 625 (1996).CrossRefGoogle Scholar

Copyright information

© The Polymer Society of Korea and Springer Nature B.V. 2018

Authors and Affiliations

  • Qurrat Ul Ain
    • 1
  • Young Sun Woo
    • 1
  • Jee Young Chung
    • 1
  • Yong-Hee Kim
    • 1
  1. 1.Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Room 908, IT/BT buildingHanyang UniversitySeoulKorea

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