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Applied Biochemistry and Biotechnology

, Volume 186, Issue 1, pp 245–255 | Cite as

MicroRNA-499a-5p Promotes Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells to Cardiomyocytes

  • Vajiheh Neshati
  • Samaneh Mollazadeh
  • Bibi Sedigheh Fazly Bazzaz
  • Antoine A. F. de Vries
  • Majid Mojarrad
  • Hojjat Naderi-Meshkin
  • Zeinab Neshati
  • Mahdi Mirahmadi
  • Mohammad Amin Kerachian
Article

Abstract

Since the adult mammalian heart has limited regenerative capacity, cardiac trauma, disease, and aging cause permanent loss of contractile tissue. This has fueled the development of stem cell-based strategies to provide the damaged heart with new cardiomyocytes. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are capable of self-renewal and differentiation into cardiomyocytes, albeit inefficiently. MicroRNAs (miRNAs, miRs) are non-coding RNAs that have the potential to control stem cell fate decisions and are employed in cardiac regeneration and repair. In this study, we tested the hypothesis that overexpression of miR-499a induces cardiomyogenic differentiation in BM-MSCs. Human BM-MSCs (hBM-MSCs) were transduced with lentiviral vectors encoding miR-499a-3p or miR-499a-5p and analyzed by immunostaining and western blotting methods 14 days post-transduction. MiR-499a-5p-transduced cells adopted a polygonal/rod-shaped (myocyte-like) phenotype and showed an increase in the expression of the cardiomyocyte markers α-actinin and cTnI, as cardiogenic differentiation markers. These results indicate that miR-499a-5p overexpression promotes the cardiomyogenic differentiation of hBM-MSCs and may thereby increase their therapeutic efficiency in cardiac regeneration.

Keywords

MicroRNA-499a Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) Cardiomyogenesis Lentiviral vectors 

Notes

Acknowledgements

The authors are grateful to the members of the Laboratory of Experimental Cardiology, Leiden University Medical Center, Leiden, the Netherlands, for their assistance in lentiviral vector construction and production and their helpful cooperation.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Moran, A. E., Forouzanfar, M. H., Roth, G. A., Mensah, G. A., Ezzati, M., Flaxman, A., Murray, C. J. L., & Naghavi, M. (2014). The global burden of ischemic heart disease in 1990 and 2010: the global burden of disease 2010 study. Circulation, 129(14), 1493–1501.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Passier, R., van Laake, L. W., & Mummery, C. L. (2008). Stem-cell-based therapy and lessons from the heart. Nature, 453(7193), 322–329.CrossRefPubMedGoogle Scholar
  3. 3.
    Song, K., Wang, Z., & Li, W. (2013). In vitro culture, determination, and directed differentiation of adult adipose-derived stem cells towards cardiomyocyte-like cells induced by angiotensin II. Appl Biochem Biotechnol, 170, 459–470.CrossRefPubMedGoogle Scholar
  4. 4.
    Pontikoglou, C., & Deschaseaux, F. (2011). Bone marrow mesenchymal stem cells: biological properties and their role in hematopoiesis and hematopoietic stem cell transplantation. Stem Cell Review, 7(3), 569–589.CrossRefGoogle Scholar
  5. 5.
    Shi, S., Wu, X., Wang, X., Hao, W., Miao, H., Zhen, L., et al. (2016). Differentiation of bone marrow mesenchymal stem cells to cardiomyocyte-like cells is regulated by the combined low dose treatment of transforming growth factor-β1 and 5-azacytidine. Stem Cells International, 2016, 3816256.Google Scholar
  6. 6.
    Cao, F., Niu, L. L., Meng, L., Zhao, L. X., Zheng, M., Yue, W., Bai, C. X., Jia, G. L., & Pei, X. T. (2004). Cardiomyocyte-like differentiation of human bone marrow mesenchymal stem cells after exposure of 5-azacytidine in vitro. Shi Yan Sheng Wu Xue Bao, 37(2), 118–124.PubMedGoogle Scholar
  7. 7.
    Xie, X. J., Wang, J. A., Cao, J., & Zhang, X. (2006). Differentiation of bone marrow mesenchymal stem cells induced by myocardial medium under hypoxic conditions [Internet]. Acta Pharmacologica Sinica, 27(9), 1153–1158.CrossRefPubMedGoogle Scholar
  8. 8.
    Wen, Z., Zheng, S., Zhou, C., Yuan, W., Wang, J., & Wang, T. (2012). Bone marrow mesenchymal stem cells for post-myocardial infarction cardiac repair: microRNAs as novel regulators. Journal of Cellular and Molecular Medicine, 16(4), 657–671.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cai, M., Shen, R., Song, L., Lu, M., Wang, J., Zhao, S., Tang, Y., Meng, X., Li, Z., & He, Z. X. (2016). Bone marrow mesenchymal stem cells (BM-MSCs) improve heart function in swine myocardial infarction model through paracrine effects. Scientific Reports, 6(1), 28250.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Barth, A. S., Kizana, E., Smith, R. R., Terrovitis, J., Dong, P., Leppo, M. K., Terrovitis, J., Dong, P., Leppo, M. K., Zhang, Y., Miake, J., Olson, E. N., Schneider, J. W., Abraham, M. R., & Marbán, E. (2008). Lentiviral vectors bearing the cardiac promoter of the Na+-Ca2+ exchanger report cardiogenic differentiation in stem cells. Molecular therapy: the Journal of the American Society of Gene Therapy, 16(5), 957–964.CrossRefGoogle Scholar
  11. 11.
    Ivey, K.N., Srivastava. D. (2015). microRNAs as developmental regulators. Cold Spring Harbor Perspectives in Biology, 1–9.Google Scholar
  12. 12.
    Zhao, Y., Samal, E., & Srivastava, D. (2005). Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature, 436(7048), 214–220.CrossRefPubMedGoogle Scholar
  13. 13.
    Ivey, K. N., Muth, A., Arnold, J., King, F. W., Yeh, R. F., Fish, J. E., Hsiao, E. C., Schwartz, R. J., Conklin, B. R., Bernstein, H. S., & Srivastava, D. (2008). MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. Cell Stem Cell, 2(3), 219–229.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Thum, T., Galuppo, P., Wolf, C., Fiedler, J., Kneitz, S., Laake, L. W., et al. (2007). MicroRNAs in the human heart a clue to fetal gene reprogramming in heart failure. Circulation, 116(3), 258–267.CrossRefPubMedGoogle Scholar
  15. 15.
    Morton, S.U., Scherz, P.J., Cordes, K.R., Ivey, K.N., Stainier, D.Y.R., Srivastava, D. (2008). microRNA-138 modulates cardiac patterning during embryonic development. Proceedings of the National Academy of Sciences of the United States of America, 105(46), 17830–5.105:17830–5.Google Scholar
  16. 16.
    van Rooij, E., Sutherland, L. B., Qi, X., Richardson, J. A., Hill, J., & Olson, E. N. (2007). Control of stress-dependent cardiac growth and gene expression by a microRNA. Science, 316(5824), 575–579.CrossRefPubMedGoogle Scholar
  17. 17.
    Fu, J. D., Rushing, S. N., Lieu, D. K., Chan, C. W., Kong, C. W., Geng, L., Wilson, K. D., Chiamvimonvat, N., Boheler, K. R., Wu, J. C., Keller, G., Hajjar, R. J., & Li, R. A. (2011). Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes. PLoS One, 6(11), e27417.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wilson, K.D., Hu, S., Venkatasubrahmanyam, S., Fu, J., Sun, N., Abilez, O.J., et al. (2010). Differentiation of human embryonic stem cells role for miR-499. Circulation. Cardiovascular genetics, 3(5), 426–435.Google Scholar
  19. 19.
    Hosoda, T., Zheng, H., Cabral-Da-Silva, M., Sanada, F., Ide-Iwata, N., Ogórek, B., Zheng, H., Cabral-da-Silva, M., Sanada, F., Ide-Iwata, N., Ogórek, B., Ferreira-Martins, J., Arranto, C., D'Amario, D., del Monte, F., Urbanek, K., D'Alessandro, D. A., Michler, R. E., Anversa, P., Rota, M., Kajstura, J., & Leri, A. (2011). Human cardiac stem cell differentiation is regulated by a mircrine mechanism. Circulation, 123(12), 1287–1296.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Sluijter, J. P. G., Van Mil, A., Van Vliet, P., Metz, C. H. G., Liu, J., & Pieter, A. (2010). MicroRNA-1 and -499 regulate differentiation and proliferation in human-derived cardiomyocyte progenitor cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(4), 859–868.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang, L. l., Liu, J. j., Liu, F., Liu, W. h., Wang, Y. s., Zhu, B., & Yu, B. (2012). MiR-499 induces cardiac differentiation of rat mesenchymal stem cells through wnt/β-catenin signaling pathway. Biochemical and Biophysical Research Communications, 420(4), 875–881.CrossRefPubMedGoogle Scholar
  22. 22.
    Bidkhori, H. R., Ahmadiankia, N., Matin, M. M., Heirani-tabasi, A., Farshchian, M., Naderi-meshkin, H., Shahriyari, M., Dastpak, M., & Bahrami, A. R. (2016). Chemically primed bone-marrow derived mesenchymal stem cells show enhanced expression of chemokine receptors contributed to their migration capability. Iran J Basic Med Sci, 40(7), 730–741.Google Scholar
  23. 23.
    Bingen, B. O., Neshati, Z., Aska, S. A. F., Kazbanov, I. V., Ypey, D. L., et al. (2013). Atrium-specific Kir3.x determines inducibility, dynamics, and termination of fibrillation by regulating restitution-driven alternans. Circulation, 128(25), 2732–2744.CrossRefPubMedGoogle Scholar
  24. 24.
    Tian, J., An, X., & Niu, L. (2017). Role of microRNAs in cardiac development and disease. Experimental and Therapeutic Medicine, 13(1), 3–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Huang, F., Tang, L., Fang, Z., Hu, X., Pan, J., & Zhou, S. (2013). miR-1-mediated induction of cardiogenesis in mesenchymal stem cells via downregulation of Hes-1. BioMed Research International, 2013, 2013–2022.Google Scholar
  26. 26.
    Li, Y., Lu, J., Bao, X., Wang, X., Wu, J., & Li, X. (2016). MiR-499-5p protects cardiomyocytes against ischaemic injury via anti-apoptosis by targeting PDCD4. Oncotarget, 7(24), 35607–35617.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Li, X., Wang, J., Jia, Z., Cui, Q., Zhang, C., Wang, W., Chen, P., Ma, K., & Zhou, C. (2013). MiR-499 regulates cell proliferation and apoptosis during late-stage cardiac differentiation via Sox6 and cyclin D1. PLoS One, 8(9), e74504.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zhan, J., Jiao, D., Wang, Y., Song, J., Wu, J., Wu, L., et al (2017) Integrated microRNA and gene expression profiling reveals the crucial miRNAs in curcumin anti-lung cancer cell invasion. Thoracic Cancer, 1–10.Google Scholar
  29. 29.
    Ferreira-cornwellm M.C., Luo, Y., Narula, N., Lenox, J.M., Lieberman, M., Radice, G.L .(2002). Remodeling the intercalated disc leads to cardiomyopathy in mice misexpressing cadherins in the heart. Journal of Cell Science, 115, 1623–1634.Google Scholar
  30. 30.
    Xu, Z., Han, Y., Liu, J., Jiang, F., Hu, H., Wang, Y., et al. (2015). MiR-135b-5p and MiR-499a-3p promote cell proliferation and migration in atherosclerosis by directly targeting MEF2C. Scientific Reports, 5, 1–15.CrossRefGoogle Scholar
  31. 31.
    Desjardins, A. C., & Naya, F. J. (2016). The function of the MEF2 family of transcription factors in cardiac development, cardiogenomics, and direct reprogramming. Journal of cardiovascular development and disease, 3, 1–23.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Vajiheh Neshati
    • 1
  • Samaneh Mollazadeh
    • 1
  • Bibi Sedigheh Fazly Bazzaz
    • 2
  • Antoine A. F. de Vries
    • 3
  • Majid Mojarrad
    • 4
    • 5
  • Hojjat Naderi-Meshkin
    • 6
  • Zeinab Neshati
    • 7
  • Mahdi Mirahmadi
    • 4
  • Mohammad Amin Kerachian
    • 4
    • 5
  1. 1.Biotechnology Research Center, Institute of Pharmaceutical TechnologyMashhad University of Medical SciencesMashhadIran
  2. 2.Biotechnology Research Center, School of PharmacyMashhad University of Medical SciencesMashhadIran
  3. 3.Department of CardiologyLeiden University Medical CenterLeidenThe Netherlands
  4. 4.Department of Medical Genetics, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  5. 5.Medical Genetics Research Center, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  6. 6.Stem Cell and Regenerative Medicine Research DepartmentIranian Academic Center for Education, Culture Research (ACECR)MashhadIran
  7. 7.Department of Biology, Faculty of ScienceFerdowsi University of MashhadMashhadIran

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