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

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 well-known 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.

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Correspondence to Yong-Hee Kim.

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Acknowledgments: This research was partially supported by grants from the National Research Foundation of Korea (NRF) grant funded by the Korea government (2015R1A2A1A09003019) and Bio & Medical technology development program (NRF-2017M3A9F5029655), the Brain Korea 21 plus program (22A20130011095), and the Korean Health Technology R&D project through the Ministry of Health and Welfare (HI17C0888).

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Ain, Q.U., Woo, Y.S., Chung, J.Y. et al. Regeneration of Anti-Hypoxic Myocardial Cells by Transduction of Mesenchymal Stem Cell-Derived Exosomes Containing Tat-Metallothionein Fusion Proteins. Macromol. Res. 26, 709–716 (2018). https://doi.org/10.1007/s13233-018-6101-5

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  • DOI: https://doi.org/10.1007/s13233-018-6101-5

Keywords

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