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Delivery of Exogenous miR-124 to Glioblastoma Multiform Cells by Wharton’s Jelly Mesenchymal Stem Cells Decreases Cell Proliferation and Migration, and Confers Chemosensitivity

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Abstract

MicroRNAs (miRs) are potential therapeutic targets in glioblastoma multiforme (GBM), but the difficulties associated with their delivery to tumor target cells have hampered their widespread use. Mesenchymal stem cells (MSCs) can migrate to the sites of cancers, including GBM and exert anti-tumor effects. In this study, it is shown that Wharton’s jelly-MSCs (WJ-MSCs) have the ability to deliver exogenous miRs to GBM cells and the functional impact of this delivery is characterized. It is found that the labeled miR-124, as an example for miR of interest, can be successfully delivered with WJ-MSCs to U87 GBM cells via dependent or exosome-independent processes. It is demonstrated that the delivered exogenous miR-124 significantly decreases the luciferase activity of the target gene CDK6. In addition, the delivered miR-124 enhances the chemosensitivity of GBM cells to temozolomide and decreases the migration of GBM cells. These results suggest that the use of exogenous miRNA delivery with the derived exosomes from WJ-MSCs may provide a novel approach for miRNA replacement therapy in GBM cancers.

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References

  1. Furnari, F. B., Fenton, T., Bachoo, R. M., et al. (2007). Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes & Development, 21, 2683–2710.

    Article  CAS  Google Scholar 

  2. Desjardins, A., Rich, J. N., Quinn, J. A., et al. (2005). Chemotherapy and novel therapeutic approaches in malignant glioma. Frontiers in Bioscience, 10, 2645–2668.

    Article  CAS  PubMed  Google Scholar 

  3. Giese, A., Bjerkvig, R., Berens, M., & Westphal, M. (2003). Cost of migration: invasion of malignant gliomas and implications for treatment. Journal of Clinical Oncology, 21, 1624–1636.

    Article  CAS  PubMed  Google Scholar 

  4. Louis, D., Posner, J., Jacobs, T., & Kaplan, R. (2000). Report of the brain tumor progress review group. Leesburg: National Institute of Neurological Disorders and Stroke, pp. 1–96.

    Google Scholar 

  5. Yamada, R., & Nakano, I. (2012). Glioma stem cells: their role in chemoresistance. World Neurosurgery, 77, 237–240.

    Article  PubMed  Google Scholar 

  6. Nakamizo, A., Marini, F., Amano, T., et al. (2005). Human bone marrow–derived mesenchymal stem cells in the treatment of gliomas. Cancer Research, 65, 3307–3318.

    Article  CAS  PubMed  Google Scholar 

  7. Abba, M., Mudduluru, G., & Allgayer, H. (2012). MicroRNAs in cancer: small molecules, big chances. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 12, 733–743.

    CAS  Google Scholar 

  8. Li, Y., Guessous, F., Zhang, Y., et al. (2009). MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Research, 69, 7569–7576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Godlewski, J., Nowicki, M. O., Bronisz, A., et al. (2008). Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Research, 68, 9125–9130.

    Article  CAS  PubMed  Google Scholar 

  10. Bao, L., Hazari, S., Mehra, S., Kaushal, D., Moroz, K., & Dash, S. (2012). Increased expression of P-glycoprotein and doxorubicin chemoresistance of metastatic breast cancer is regulated by miR-298. The American Journal of Pathology, 180, 2490–2503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lawler, S., & Chiocca, E. A. (2009). Emerging functions of microRNAs in glioblastoma. Journal of Neuro-Oncology, 92, 297–306.

    Article  CAS  PubMed  Google Scholar 

  12. An, L., Liu, Y., Wu, A., & Guan, Y. (2013). microRNA-124 inhibits migration and invasion by down-regulating ROCK1 in glioma. PLoS One, 8, e69478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wei, J., Wang, F., Kong, L. Y., et al. (2013). MiR-124 inhibits STAT3 signaling to enhance T cell–mediated immune clearance of glioma. Cancer Research, 73, 3913–3926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen, S. M., Chou, W. C., Hu, L. Y., et al. (2015). The effect of MicroRNA-124 over expression on anti-tumor drug sensitivity. PLoS One, 10, e0128472.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Fowler, A., Thomson, D., Giles, K., et al. (2011). miR-124a is frequently down-regulated in glioblastoma and is involved in migration and invasion. European Journal of Cancer, 47, 953–963.

    Article  CAS  PubMed  Google Scholar 

  16. Silber, J., Lim, D. A., Petritsch, C., et al. (2008). miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Medicine, 6, 14.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Shi, Z., Chen, Q., Li, C., et al. (2014). MiR-124 governs glioma growth and angiogenesis and enhances chemosensitivity by targeting R-Ras and N-Ras. Neuro-Oncology, 16(10), 1341–1353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shah, K. (2012). Mesenchymal stem cells engineered for cancer therapy. Advanced Drug Delivery Reviews, 64, 739–748.

    Article  CAS  PubMed  Google Scholar 

  19. Sun, X. Y., Nong, J., Qin, K., Warnock, G. L., & Dai, L. J. (2011). Mesenchymal stem cell-mediated cancer therapy: a dual-targeted strategy of personalized medicine. World Journal Stem Cells, 3, 96–103.

    Article  Google Scholar 

  20. Kim, D. W., Staples, M., Shinozuka, K., Pantcheva, P., Kang, S. D., & Borlongan, C. V. (2013). Wharton’s jelly-derived mesenchymal stem cells: phenotypic characterization and optimizing their therapeutic potential for clinical applications. International Journal of Molecular Sciences, 14, 11692–11712.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hsieh, J. Y., Wang, H. W., Chang, S. J., et al. (2013). Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PloS One, 8, e72604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu, S., Hou, K. D., Yuan, M., et al. (2014). Characteristics of mesenchymal stem cells derived from Wharton’s jelly of human umbilical cord and for fabrication of non-scaffold tissue-engineered cartilage. Journal of Bioscience and Bioengineering, 117, 229–235.

    Article  CAS  PubMed  Google Scholar 

  23. Ng, F., Boucher, S., Koh, S., et al. (2008). PDGF, TGF-β, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood, 112, 295–307.

    Article  CAS  PubMed  Google Scholar 

  24. Pittenger, M. F., Mackay, A. M., Beck, S. C., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284, 143–147.

    Article  CAS  PubMed  Google Scholar 

  25. Greco, S. J., & Rameshwar, P. (2012). Mesenchymal stem cells in drug/gene delivery: implications for cell therapy. Therapeutic Delivery, 3, 997–1004.

    Article  CAS  PubMed  Google Scholar 

  26. Matuskova, M., Hlubinova, K., Pastorakova, A., et al. (2010). HSV-tk expressing mesenchymal stem cells exert bystander effect on human glioblastoma cells. Cancer Letters, 290, 58–67.

    Article  CAS  PubMed  Google Scholar 

  27. Mittelbrunn, M., Gutiérrez-Vázquez, C., Villarroya-Beltri, C., et al. (2011). Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nature Communications, 2, 282.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kosaka, N., Iguchi, H., Yoshioka, Y., Takeshita, F., Matsuki, Y., & Ochiya, T. (2010). Secretory mechanisms and intercellular transfer of microRNAs in living cells. Journal of Biological Chemistry, 285, 17442–17452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Collino, F., Deregibus, M. C., Bruno, S., et al. (2010). Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One, 5, e11803.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Broderick, J. A., & Zamore, P. D. (2011). MicroRNA therapeutics. Gene Therapy, 18, 1104–1110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Karussis, D., Kassis, I., Kurkalli, B. G. S., & Slavin, S. (2008). Immunomodulation and neuroprotection with mesenchymal bone marrow stem cells (MSCs): a proposed treatment for multiple sclerosis and other neuroimmunological/neurodegenerative diseases. Journal of the Neurological Sciences, 265, 131–135.

    Article  CAS  PubMed  Google Scholar 

  32. Mohr, A., Lyons, M., Deedigan, L., et al. (2008). Mesenchymal stem cells expressing TRAIL lead to tumour growth inhibition in an experimental lung cancer model. Journal of Cellular and Molecular Medicine, 12, 2628–2643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Amano, S., Li, S., Gu, C., et al. (2009). Use of genetically engineered bone marrow-derived mesenchymal stem cells for glioma gene therapy. International Journal of Oncology, 35, 1265.

    CAS  PubMed  Google Scholar 

  34. Park, S. A., Ryu, C. H., Kim, S. M., et al. (2011). CXCR4-transfected human umbilical cord blood-derived mesenchymal stem cells exhibit enhanced migratory capacity toward gliomas. International Journal of Oncology, 38, 97.

    CAS  PubMed  Google Scholar 

  35. Lim, P. K., Bliss, S. A., Patel, S. A., et al. (2011). Gap junction–mediated import of MicroRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. Cancer Research, 71, 1550–1560.

    Article  CAS  PubMed  Google Scholar 

  36. Bader, A. G., Brown, D., & Winkler, M. (2010). The promise of microRNA replacement therapy. Cancer Research, 70, 7027–7030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nana-Sinkam, S. P., & Croce, C. M. (2011). MicroRNAs as therapeutic targets in cancer. Translational Research, 157, 216–225.

    Article  CAS  PubMed  Google Scholar 

  38. Yoo, A. S., Sun, A. X., Li, L., et al. (2011). MicroRNA-mediated conversion of human fibroblasts to neurons. Nature, 476, 228–231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cheng, L. C., Pastrana, E., Tavazoie, M., & Doetsch, F. (2009). miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nature Neuroscience, 12, 399–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lee, H. K., Finniss, S., Cazacu, S., et al. (2013). Mesenchymal stem cells deliver synthetic microRNA mimics to glioma cells and glioma stem cells and inhibit their cell migration and self-renewal. Oncotarget, 4, 346–361.

    PubMed  PubMed Central  Google Scholar 

  41. Katakowski, M., Buller, B., Zheng, X., et al. (2013). Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Letters, 335, 201–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Munoz, J. L., Bliss, S. A., Greco, S. J., Ramkissoon, S. H., Ligon, K. L., & Rameshwar, P. (2013). Delivery of functional anti-miR-9 by mesenchymal stem cell–derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Molecular Therapy—Nucleic Acids, 2, e126.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Blum, R., Jacob-Hirsch, J., Amariglio, N., Rechavi, G., & Kloog, Y. (2005). Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1α, causing glycolysis shutdown and cell death. Cancer Research, 65, 999–1006.

    CAS  PubMed  Google Scholar 

  44. Zou, C., Xu, Q., Mao, F., et al. (2012). MiR-145 inhibits tumor angiogenesis and growth by N-RAS and VEGF. Cell Cycle, 11, 2137–2145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ryan, J. M., Barry, F. P., Murphy, J. M., & Mahon, B. P. (2005). Mesenchymal stem cells avoid allogeneic rejection. Journal of Inflammation, 2, 8.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Pileggi, A., Xu, X., Tan, J., & Ricordi, C. (2013). Mesenchymal stromal (stem) cells to improve solid organ transplant outcome: lessons from the initial clinical trials. Current Opinion in Organ Transplantation, 18, 672.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang, H. S., Hung, S. C., Peng, S. T., et al. (2004). Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells, 22, 1330–1337.

    Article  PubMed  Google Scholar 

  48. Drela, K., Lech, W., Figiel-Dabrowska, A., et al. (2016). Enhanced neuro-therapeutic potential of Wharton’s Jelly–derived mesenchymal stem cells in comparison with bone marrow mesenchymal stem cells culture. Cytotherapy, 18, 497–509.

    Article  CAS  PubMed  Google Scholar 

  49. de Castro, J. V., Gomes, E. D., Granja, S., et al. (2017). Impact of mesenchymal stem cells’ secretome on glioblastoma pathophysiology. Journal of Translational Medicine, 15, 200.

    Article  Google Scholar 

  50. Wang, B., Yao, K., Huuskes, B. M., et al. (2016). Mesenchymal stem cells deliver exogenous microRNA-let7c via exosomes to attenuate renal fibrosis. Molecular Therapy, 24, 1290–1301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li, X., Liu, L., Yang, J., et al. (2016). Exosome derived from human umbilical cord mesenchymal stem cell mediates mir-181c attenuating burn-induced excessive inflammation. EBioMedicine, 8, 72–82.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work is a part of PhD thesis of Samaneh Sharif that is financially supported by the Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

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Authors and Affiliations

  1. Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

    S. Sharif & M. H. Ghahremani

  2. Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    M. H. Ghahremani

  3. Department of Haematology, Tarbiat Modares University, Tehran, Iran

    M. Soleimani

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  1. S. Sharif
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Correspondence to M. H. Ghahremani or M. Soleimani.

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Sharif, S., Ghahremani, M.H. & Soleimani, M. Delivery of Exogenous miR-124 to Glioblastoma Multiform Cells by Wharton’s Jelly Mesenchymal Stem Cells Decreases Cell Proliferation and Migration, and Confers Chemosensitivity. Stem Cell Rev and Rep 14, 236–246 (2018). https://doi.org/10.1007/s12015-017-9788-3

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