Gene Delivery Approaches for Mesenchymal Stem Cell Therapy: Strategies to Increase Efficiency and Specificity

Abstract

A significant number of clinical trials have been undertaken to explore the use of mesenchymal stem cells (MSCs) for the treatment of several diseases such as Crohn’s disease, diabetes, bone defects, myocardial infarction, stroke etc., Due to their efficiency in homing to the tissue injury sites, their differentiation potential, the capability to secrete a large amount of trophic factors and their immunomodulatory effects, MSCs are becoming increasingly popular and expected to be one of the promising therapeutic approaches. However, challenges associated with the isolation of pure MSC populations, their culture and expansion, specific phenotypic characterization, multi-potential differentiation and challenges of efficient transplantation limit their usage. The current strategies of cell-based therapies emphasize introducing beneficial genes, which will improve the therapeutic ability of MSCs and have better homing efficiency. The continuous improvement in gene transfer technologies has broad implications in stem cell biology. Although viral vectors are efficient vehicles for gene delivery, construction of viral vectors with desired genes, their safety and immunogenicity limit their use in clinical applications. We review current gene delivery approaches, including viral and plasmid vectors, for transfecting MSC with beneficial genes. The review also discusses the use of a few emerging technologies that could be used to improve the transfer/induction of desirable genes for cell therapy.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. 1.

    Avasthi, S., Srivastava, R., Singh, A., et al. (2008). Stem cell: past, present and future–a review article. Internet Journal of Medical Update, 3(1), 22–31.

    Google Scholar 

  2. 2.

    Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Nadig, R. R. (2009). Stem cell therapy-hype or hope? A review. Journal of Conservative Dentistry, 12(4), 131.

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Ullah, I., Subbarao, R. B., & Rho, G. J. (2015). Human mesenchymal stem cells-current trends and future prospective. Bioscience Reports, 35(2), e00191.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. 5.

    Lo, B., & Parham, L. (2009). Ethical issues in stem cell research. Endocrine Reviews, 30(3), 204–213.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Correia, A. S., Anisimov, S. V., Li, J. Y., et al. (2005). Stem cell-based therapy for Parkinson’s disease. Annals of Medicine, 37(7), 487–498.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Zhang, J., Huang, X., Wang, H., et al. (2015). The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem Cell Research & Therapy, 6(1), 234.

    Article  Google Scholar 

  8. 8.

    Aiuti, A., Slavin, S., Aker, M., et al. (2002). Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science, 296(5577), 2410–2413.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Sun, Q., Zhang, Z., & Sun, Z. (2014). The potential and challenges of using stem cells for cardiovascular repair and regeneration. Genes & Diseases, 1(1), 113–119.

    Article  Google Scholar 

  10. 10.

    Jiang, Y., Jahagirdar, B. N., Reinhardt, R. L., et al. (2002). Pluripotency of mesenchymal stem cells derived from adult marrow. Nature, 418(6893), 41–49.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Mackay, A., Beck, S., Jaiswal, R., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284(5411), 143–147.

    PubMed  Article  Google Scholar 

  12. 12.

    Tremain, N., Korkko, J., Ibberson, D., et al. (2001). MicroSAGE analysis of 2,353 expressed genes in a single cell-derived colony of undifferentiated human mesenchymal stem cells reveals mRNAs of multiple cell lineages. Stem Cells, 19(5), 408–418.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Petersen, B., Bowen, W., Patrene, K., et al. (1999). Bone marrow as a potential source of hepatic oval cells. Science, 284(5417), 1168–1170.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Schwartz, R. E., Reyes, M., Koodie, L., et al. (2002). Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. The Journal of Clinical Investigation, 109(10), 1291–1302.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Rose, R. A., Keating, A., & Backx, P. H. (2008). Do mesenchymal stromal cells transdifferentiate into functional cardiomyocytes? Circulation Research, 103(9), 120.

    Article  CAS  Google Scholar 

  16. 16.

    Pijnappels, D. A., Schalij, M. J., Ramkisoensing, A. A., et al. (2008). Forced alignment of mesenchymal stem cells undergoing cardiomyogenic differentiation affects functional integration with cardiomyocyte cultures. Circulation Research, 103(2), 167–176.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Tropel, P., Platet, N., Platel, J. C., et al. (2006). Functional neuronal differentiation of bone marrow-derived mesenchymal stem cells. Stem Cells, 24(12), 2868–2876.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Cogle, C. R., Yachnis, A. T., Laywell, E. D., et al. (2004). Bone marrow transdifferentiation in brain after transplantation: a retrospective study. The Lancet, 363(9419), 1432–1437.

    CAS  Article  Google Scholar 

  19. 19.

    Lindvall, O., Kokaia, Z., & Martinez-Serrano, A. (2004). Stem cell therapy for human neurodegenerative disorders–how to make it work. Nature Medicine, 10, 42–50.

  20. 20.

    Lindvall, O., & Kokaia, Z. (2006). Stem cells for the treatment of neurological disorders. Nature, 441(7097), 1094–1096.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Amariglio, N., Hirshberg, A., Scheithauer, B. W., et al. (2009). Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Medicine, 6(2), e1000029.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Weiden, P. L., Flournoy, N., Thomas, E. D., et al. (1979). Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. New England Journal of Medicine, 300(19), 1068–1073.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Slavin, S., Or, R., Naparstek, E., et al. (1988). Cellular-mediated immunotherapy of leukemia in conjunction with autologous and allogeneic bone marrow transplantation in experimental animals and man. Blood, 72(suppl 1), 407.

    Google Scholar 

  24. 24.

    Kolb, H., Mittermuller, J., Clemm, C., et al. (1990). Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood, 76(12), 2462–2465.

    CAS  PubMed  Google Scholar 

  25. 25.

    Van Besien, K., De Lima, M., Giralt, S., et al. (1997). Management of lymphoma recurrence after allogeneic transplantation: the relevance of graft-versus-lymphoma effect. Bone Marrow Transplantation, 19(10), 977–982.

    PubMed  Article  Google Scholar 

  26. 26.

    Afessa, B., Litzow, M., & Tefferi, A. (2001). Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplantation, 28(5), 425.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Qin, Y., Guan, J., & Zhang, C. (2014). Mesenchymal stem cells: mechanisms and role in bone regeneration. Postgraduate Medical Journal, 90(1069), 643–647.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Studeny, M., Marini, F. C., Dembinski, J. L., et al. (2004). Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. Journal of the National Cancer Institute, 96(21), 1593–1603.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Stagg, J., Pommey, S., Eliopoulos, N., et al. (2006). Interferon-γ-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell. Blood, 107(6), 2570–2577.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Ye, Z., Wang, Y., Xie, H.-Y., et al. (2008). Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4+ CD25+ regulatory T cells. Hepatobiliary & Pancreatic Diseases International, 7(6), 608–614.

    Google Scholar 

  31. 31.

    Di Ianni, M., Del Papa, B., De Ioanni, M., et al. (2008). Mesenchymal cells recruit and regulate T regulatory cells. Experimental Hematology, 36(3), 309–318.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Joo, S.-Y., Cho, K.-A., Jung, Y.-J., et al. (2010). Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner. Cytotherapy, 12(3), 361–370.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Madec, A., Mallone, R., Afonso, G., et al. (2009). Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells. Diabetologia, 52(7), 1391–1399.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Keating, A. (2008). How do mesenchymal stromal cells suppress T cells? Cell Stem Cell, 2(2), 106–108.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Di Nicola, M., Carlo-Stella, C., Magni, M., et al. (2002). Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood, 99(10), 3838–3843.

    PubMed  Article  Google Scholar 

  36. 36.

    Ren, G., Zhang, L., Zhao, X., et al. (2008). Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell, 2(2), 141–150.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Meisel, R., Zibert, A., Laryea, M., et al. (2004). Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2, 3-dioxygenase–mediated tryptophan degradation. Blood, 103(12), 4619–4621.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Marigo, I., & Dazzi, F. (2011). The immunomodulatory properties of mesenchymal stem cells. In Seminars in immunopathology. Springer. 593.

  39. 39.

    Dazzi, F., & Marelli-Berg., F. M. (2008). Mesenchymal stem cells for graft-versus-host disease: close encounters with T cells. European Journal of Immunology, 38(6), 1479–1482.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Krampera, M., Cosmi, L., Angeli, R., et al. (2006). Role for interferon-γ in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells, 24(2), 386–398.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Barry, F. P., & Murphy, J. M. (2004). Mesenchymal stem cells: clinical applications and biological characterization. The International Journal of Biochemistry & Cell Biology, 36(4), 568–584.

    CAS  Article  Google Scholar 

  42. 42.

    Mahmood, A., Lu, D., Lu, M., et al. (2003). Treatment of traumatic brain injury in adult rats with intravenous administration of human bone marrow stromal cells. Neurosurgery, 53(3), 697–703.

    PubMed  Article  Google Scholar 

  43. 43.

    Ryan, J., Barry, F., Murphy, J., et al. (2007). Interferon-γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clinical & Experimental Immunology, 149(2), 353–363.

    CAS  Article  Google Scholar 

  44. 44.

    Ryan, J. M., Barry, F. P., Murphy, J. M., et al. (2005). Mesenchymal stem cells avoid allogeneic rejection. Journal of Inflammation, 2(1), 8.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    George, J. C. (2010). Stem cell therapy in acute myocardial infarction: a review of clinical trials. Translational Research, 155(1), 10–19.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Harris, D. T. (2014). Stem cell banking for regenerative and personalized medicine. Biomedicines, 2(1), 50–79.

    PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Bang, O. Y., Lee, J. S., Lee, P. H., et al. (2005). Autologous mesenchymal stem cell transplantation in stroke patients. Annals of Neurology, 57(6), 874–882.

    PubMed  Article  Google Scholar 

  48. 48.

    Prockop, D. J. (2017). The exciting prospects of new therapies with mesenchymal stromal cells. Cytotherapy, 19(1), 1–8.

    PubMed  Article  Google Scholar 

  49. 49.

    Bang, O. Y., Kim, E. H., Cha, J. M., et al. (2016). Adult stem cell therapy for stroke: challenges and progress. Journal of Stroke, 18(3), 256.

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Steinbeck, J. A., & Studer, L. (2015). Moving stem cells to the clinic: potential and limitations for brain repair. Neuron, 86(1), 187–206.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Kim, E. H., Kim, D. H., Kim, H. R., et al. (2016). Stroke serum priming modulates characteristics of mesenchymal stromal cells by controlling the expression miRNA-20a. Cell Transplantation, 25(8), 1489–1499.

    PubMed  Article  Google Scholar 

  52. 52.

    Choi, Y. J., Li, W. Y., Moon, G. J., et al. (2010). Enhancing trophic support of mesenchymal stem cells by ex vivo treatment with trophic factors. Journal of the Neurological Sciences, 298(1), 28–34.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Efimenko, A. Y., Kochegura, T. N., Akopyan, Z. A., et al. (2015). Autologous stem cell therapy: how aging and chronic diseases affect stem and progenitor cells. BioResearch Open Access, 4(1), 26–38.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Hu, F., Wang, X., Liang, G., et al. (2013). Effects of epidermal growth factor and basic fibroblast growth factor on the proliferation and osteogenic and neural differentiation of adipose-derived stem cells. Cellular Reprogramming, 15(3), 224–232.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Mylotte, L. A., Duffy, A. M., Murphy, M., et al. (2008). Metabolic flexibility permits mesenchymal stem cell survival in an ischemic environment. Stem Cells, 26(5), 1325–1336.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    McGinley, L., McMahon, J., Strappe, P., et al. (2011). Lentiviral vector mediated modification of mesenchymal stem cells & enhanced survival in an in vitro model of ischaemia. Stem Cell Research & Therapy, 2(2), 12.

    CAS  Article  Google Scholar 

  57. 57.

    Kumar Bokara, K., Suresh Oggu, G., Josyula Vidyasagar, A., et al. (2014). Modulation of stem cell differentiation by the influence of nanobiomaterials/carriers. Current Stem Cell Research & Therapy, 9(6), 458–468.

    Article  Google Scholar 

  58. 58.

    Meisel, R., Brockers, S., Heseler, K., et al. (2011). Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2, 3-dioxygenase. Leukemia, 25(4), 648–654.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Ljungman, P., De La Camara, R., Cordonnier, C., et al. (2008). Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone Marrow Transplantation, 42(4), 227–240.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Tan, J., Wu, W., Xu, X., et al. (2012). Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA, 307(11), 1169–1177.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Khera, M., Albersen, M., & Mulhall, J. P. (2015). Mesenchymal stem cell therapy for the treatment of erectile dysfunction. The Journal of Sexual Medicine, 12(5), 1105–1106.

    PubMed  Article  Google Scholar 

  62. 62.

    Gehl, J. (2003). Electroporation: theory and methods, perspectives for drug delivery, gene therapy and research. Acta Physiologica, 177(4), 437–447.

    CAS  Article  Google Scholar 

  63. 63.

    Gresch, O., Engel, F. B., Nesic, D., et al. (2004). New non-viral method for gene transfer into primary cells. Methods, 33(2), 151–163.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Otani, K., Yamahara, K., Ohnishi, S., et al. (2009). Nonviral delivery of siRNA into mesenchymal stem cells by a combination of ultrasound and microbubbles. Journal of Controlled Release, 133(2), 146–153.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Sanchez-Antequera, Y., Mykhaylyk, O., van Til, N. P., et al. (2011). Magselectofection: an integrated method of nanomagnetic separation and genetic modification of target cells. Blood, 117(16), e171-e181.

    Article  CAS  Google Scholar 

  66. 66.

    Kim, H.-J., & Im, G.-I. (2011). Electroporation-mediated transfer of SOX trio genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of mesenchymal stem cells. Stem Cells and Development, 20(12), 2103–2114.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Ferreira, E., Potier, E., Vaudin, P., et al. (2012). Sustained and promoter dependent bone morphogenetic protein expression by rat mesenchymal stem cells after BMP-2 transgene electrotransfer. European Cells & Materials, 24(1), 18–28.

    CAS  Article  Google Scholar 

  68. 68.

    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(1), 97.

    CAS  PubMed  Google Scholar 

  69. 69.

    Ryser, M. F., Ugarte, F., Thieme, S., et al. (2008). mRNA transfection of CXCR4-GFP fusion—simply generated by PCR—results in efficient migration of primary human mesenchymal stem cells. Tissue Engineering Part C: Methods, 14(3), 179–184.

    CAS  Article  Google Scholar 

  70. 70.

    Sheyn, D., Pelled, G., Zilberman, Y., et al. (2008). Nonvirally engineered porcine adipose tissue-derived stem cells: use in posterior spinal fusion. Stem Cells, 26(4), 1056–1064.

    PubMed  Article  Google Scholar 

  71. 71.

    Rome, C., Deckers, R., & Moonen, C. T. (2008). The use of ultrasound in transfection and transgene expression. Molecular imaging II, hand book of experimental pharmacology. Springer.

  72. 72.

    Nakashima, M., Tachibana, K., Iohara, K., et al. (2003). Induction of reparative dentin formation by ultrasound-mediated gene delivery of growth/differentiation factor 11. Human Gene Therapy, 14(6), 591–597.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Li, W., Ma, N., Ong, L. L., et al. (2008). Enhanced thoracic gene delivery by magnetic nanobead-mediated vector. The Journal of Gene Medicine, 10(8), 897–909.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Li, W., Nesselmann, C., Zhou, Z., et al. (2007). Gene delivery to the heart by magnetic nanobeads. Journal of Magnetism and Magnetic Materials, 311(1), 336–341.

    CAS  Article  Google Scholar 

  75. 75.

    Bharali, D. J., Klejbor, I., Stachowiak, E. K., et al. (2005). Organically modified silica nanoparticles: a nonviral vector for in vivo gene delivery and expression in the brain. Proceedings of the National Academy of Sciences of the United States of America, 102(32), 11539–11544.

  76. 76.

    Gao, L., Nie, L., Wang, T., et al. (2006). Carbon nanotube delivery of the GFP gene into mammalian cells. ChemBioChem, 7(2), 239–242.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Guo, S., Huang, Y., Jiang, Q., et al. (2010). Enhanced gene delivery and siRNA silencing by gold nanoparticles coated with charge-reversal polyelectrolyte. ACS Nano, 4(9), 5505–5511.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Tan, W. B., Jiang, S., & Zhang, Y. (2007). Quantum-dot based nanoparticles for targeted silencing of HER2/neu gene via RNA interference. Biomaterials, 28(8), 1565–1571.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Wu, H. C., Wang, T. W., Bohn, M. C., et al. (2010). Novel magnetic hydroxyapatite nanoparticles as non-viral vectors for the glial cell line-derived neurotrophic factor gene. Advanced Functional Materials, 20(1), 67–77.

    CAS  Article  Google Scholar 

  80. 80.

    Kim, T. H., Kim, M., Eltohamy, M., et al. (2013). Efficacy of mesoporous silica nanoparticles in delivering BMP-2 plasmid DNA for in vitro osteogenic stimulation of mesenchymal stem cells. Journal of Biomedical Materials Research Part A, 101(6), 1651–1660.

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Lin, C., Wang, Y., Lai, Y., et al. (2011). Incorporation of carboxylation multiwalled carbon nanotubes into biodegradable poly (lactic-co-glycolic acid) for bone tissue engineering. Colloids and Surfaces B: Biointerfaces, 83(2), 367–375.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Baik, K. Y., Park, S. Y., Heo, K., et al. (2011). Carbon nanotube monolayer cues for osteogenesis of mesenchymal stem cells. Small, 7(6), 741–745.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Bhattacharya, M., Wutticharoenmongkol-Thitiwongsawet, P., Hamamoto, D. T., et al. (2011). Bone formation on carbon nanotube composite. Journal of Biomedical Materials Research Part A, 96(1), 75–82.

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Cellot, G., Toma, F. M., Varley, Z. K., et al. (2011). Carbon nanotube scaffolds tune synaptic strength in cultured neural circuits: novel frontiers in nanomaterial–tissue interactions. Journal of Neuroscience, 31(36), 12945–12953.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Fabbro, A., Villari, A., Laishram, J., et al. (2012). Spinal cord explants use carbon nanotube interfaces to enhance neurite outgrowth and to fortify synaptic inputs. ACS Nano, 6(3), 2041–2055.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Joydeep, D., Choi, Y.-J., Yasuda, H., et al. (2016). Efficient delivery of C/EBP beta gene into human mesenchymal stem cells via polyethylenimine-coated gold nanoparticles enhances adipogenic differentiation. Scientific Reports, 6, 37480.

  87. 87.

    Cao, X., Deng, W., Wei, Y., et al. (2011). Encapsulation of plasmid DNA in calcium phosphate nanoparticles: stem cell uptake and gene transfer efficiency. International Journal of NanoMedicine, 6, 3335–3349.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Cho, J. W., Lee, C. Y., & Ko, Y. (2012). Therapeutic potential of mesenchymal stem cells overexpressing human forkhead box A2 gene in the regeneration of damaged liver tissues. Journal of Gastroenterology and Hepatology, 27(8), 1362–1370.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Jeon, S. Y., Park, J. S., Yang, H. N., et al. (2012). Co-delivery of SOX9 genes and anti-Cbfa-1 siRNA coated onto PLGA nanoparticles for chondrogenesis of human MSCs. Biomaterials, 33(17), 4413–4423.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Kim, N. Y., Choi, Y. B., Kang, C. I., et al. (2010). An hydrophobically modified arginine peptide vector system effectively delivers DNA into human mesenchymal stem cells and maintains transgene expression with differentiation. The Journal of Gene Medicine, 12(9), 779–789.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Thakor, D. K., Teng, Y. D., Obata, H., et al. (2010). Nontoxic genetic engineering of mesenchymal stem cells using serum-compatible pullulan-spermine/DNA anioplexes. Tissue Engineering Part C: Methods, 17(2), 131–144.

    Article  CAS  Google Scholar 

  92. 92.

    Jordan, M., & Wurm, F. (2004). Transfection of adherent and suspended cells by calcium phosphate. Methods, 33(2), 136–143.

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Masotti, A., Mossa, G., Cametti, C., et al. (2009). Comparison of different commercially available cationic liposome–DNA lipoplexes: parameters influencing toxicity and transfection efficiency. Colloids and Surfaces B: Biointerfaces, 68(2), 136–144.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Ruponen, M., Rönkkö, S., Honkakoski, P., et al. (2001). Extracellular glycosaminoglycans modify cellular trafficking of lipoplexes and polyplexes. Journal of Biological Chemistry, 276(36), 33875–33880.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Rejman, J., Conese, M., & Hoekstra, D. (2006). Gene transfer by means of lipo-and polyplexes: role of clathrin and caveolae-mediated endocytosis. Journal of Liposome Research, 16(3), 237–247.

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Simões, S., Slepushkin, V., Pires, P., et al. (1999). Mechanisms of gene transfer mediated by lipoplexes associated with targeting ligands or pH-sensitive peptides. Gene Therapy, 6(11), 1798–1807.

    PubMed  Article  Google Scholar 

  97. 97.

    Wen, Y., Guo, Z., Du, Z., et al. (2012). Serum tolerance and endosomal escape capacity of histidine-modified pDNA-loaded complexes based on polyamidoamine dendrimer derivatives. Biomaterials, 33(32), 8111–8121.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Li, W., Ma, N., Ong, L. L., et al. (2007). Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells, 25(8), 2118–2127.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Kim, H. H., Choi, H. S., Yang, J. M., et al. (2007). Characterization of gene delivery in vitro and in vivo by the arginine peptide system. International Journal of Pharmaceutics, 335(1), 70–78.

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Bachrach, U. (2005). Naturally occurring polyamines: interaction with macromolecules. Current Protein and Peptide Science, 6(6), 559–566.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Azzam, T., Raskin, A., Makovitzki, A., et al. (2002). Cationic polysaccharides for gene delivery. Macromolecules, 35(27), 9947–9953.

    CAS  Article  Google Scholar 

  102. 102.

    Han, S.-W., Nakamura, C., Kotobuki, N., et al. (2008). High-efficiency DNA injection into a single human mesenchymal stem cell using a nanoneedle and atomic force microscopy. Nanomedicine: Nanotechnology, Biology and Medicine, 4(3), 215–225.

    CAS  Article  Google Scholar 

  103. 103.

    Subramanian, A., Ranganathan, P., & Diamond, S. L. (1999). Nuclear targeting peptide scaffolds for lipofection of nondividing mammalian cells. Nature Biotechnology, 17(9), 873–877.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Vallhov, H., Gabrielsson, S., Strømme, M., et al. (2007). Mesoporous silica particles induce size dependent effects on human dendritic cells. Nano Letters, 7(12), 3576–3582.

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Simões, S., Filipe, A., Faneca, H., et al. (2005). Cationic liposomes for gene delivery. Expert Opinion on Drug Delivery, 2(2), 237–254.

    PubMed  Article  Google Scholar 

  106. 106.

    Wang, W., Xu, X., Li, Z., et al. (2014). Genetic engineering of mesenchymal stem cells by non-viral gene delivery. Clinical Hemorheology and Microcirculation, 58(1), 19–48.

    PubMed  Google Scholar 

  107. 107.

    Nowakowski, A., Andrzejewska, A., Janowski, M., et al. (2013). Genetic engineering of stem cells for enhanced therapy. Acta Neurobiologiae Experimentalis, 73(1), 1–18.

    PubMed  Google Scholar 

  108. 108.

    Dahlberg, J. (1987). An overview of retrovirus replication and classification. Advances in Veterinary Science and Comparative Medicine, 32, 1–35.

    Google Scholar 

  109. 109.

    Aiuti, A., Cattaneo, F., Galimberti, S., et al. (2009). Gene therapy for immunodeficiency due to adenosine deaminase deficiency. New England Journal of Medicine, 360(5), 447–458.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Laker, C., Meyer, J., Schopen, A., et al. (1998). Host cis-mediated extinction of a retrovirus permissive for expression in embryonal stem cells during differentiation. Journal of Virology, 72(1), 339–348.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Challita, P.-M., & Kohn, D. B. (1994). Lack of expression from a retroviral vector after transduction of murine hematopoietic stem cells is associated with methylation in vivo. Proceedings of the National Academy of Sciences, 91(7), 2567–2571.

  112. 112.

    Hacein-Bey-Abina, S., Hauer, J., Lim, A., et al. (2010). Efficacy of gene therapy for X-linked severe combined immunodeficiency. New England Journal of Medicine, 363(4), 355–364.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Huang, S., & Terstappen, L. (1994). Lymphoid and myeloid differentiation of single human CD34+, HLA-DR+, CD38-hematopoietic stem cells. Blood, 83(6), 1515–1526.

    CAS  PubMed  Google Scholar 

  114. 114.

    Naldini, L., Blomer, U., Gallay, P., et al. (1996). In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science, 272(5259), 263.

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Hu, J., Lang, Y., Zhang, T., et al. (2016). Lentivirus-mediated PGC-1α overexpression protects against traumatic spinal cord injury in rats. Neuroscience, 328, 40–49.

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Xiang, Q., Hong, D., Liao, Y., et al. (2016). Overexpression of gremlin1 in mesenchymal stem cells improves hindlimb ischemia in mice by enhancing cell survival. Journal of Cellular Physiology, 232(5), 996–1007.

    PubMed  Article  CAS  Google Scholar 

  117. 117.

    De Melo, S. M., Bittencourt, S., Ferrazoli, E. G., et al. (2015). The anti-tumor effects of adipose tissue mesenchymal stem cell transduced with HSV-Tk gene on U-87-driven brain tumor. PLoS One, 10(6), e0128922.

  118. 118.

    Cartier, N., & Aubourg, P. (2010). Hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy in X-Linked adrenoleukodystrophy. Brain Pathology, 20(4), 857–862.

    PubMed  Article  Google Scholar 

  119. 119.

    Cavazzana-Calvo, M., Payen, E., Negre, O., et al. (2010). Transfusion independence and HMGA2 activation after gene therapy of human [bgr]-thalassaemia. Nature, 467(7313), 318–322.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Aiuti, A., Biasco, L., Scaramuzza, S., et al. (2013). Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science, 341(6148), 1233151.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  121. 121.

    Biffi, A., Montini, E., Lorioli, L., et al. (2013). Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science, 341(6148), 1233158.

    PubMed  Article  CAS  Google Scholar 

  122. 122.

    Tomás, H. A., Rodrigues, A. F., Alves, P. M., et al. (2013). Lentiviral gene therapy vectors: Challenges and future directions. InTech.

  123. 123.

    Ke, J., Zheng, L., & Cheung, L. (2011). Orthopaedic gene therapy using recombinant adeno-associated virus vectors. Archives of Oral Biology, 56(7), 619–628.

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Zaiss, A.-K., Liu, Q., Bowen, G. P., et al. (2002). Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors. Journal of Virology, 76(9), 4580–4590.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Wright, J. F. (2009). Transient transfection methods for clinical adeno-associated viral vector production. Human Gene Therapy, 20(7), 698–706.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Frisch, J., Venkatesan, J. K., Rey-Rico, A., et al. (2014). Influence of insulin-like growth factor I overexpression via recombinant adeno-associated vector gene transfer upon the biological activities and differentiation potential of human bone marrow-derived mesenchymal stem cells. Stem Cell Research & Therapy, 5(4), 103.

    Article  Google Scholar 

  127. 127.

    Frisch, J., Venkatesan, J. K., Rey-Rico, A., et al. (2014). Determination of the chondrogenic differentiation processes in human bone marrow-derived mesenchymal stem cells genetically modified to overexpress transforming growth factor-β via recombinant adeno-associated viral vectors. Human Gene Therapy, 25(12), 1050–1060.

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Venkatesan, J. K., Ekici, M., Madry, H., et al. (2012). SOX9 gene transfer via safe, stable, replication-defective recombinant adeno-associated virus vectors as a novel, powerful tool to enhance the chondrogenic potential of human mesenchymal stem cells. Stem Cell Research & Therapy, 3(3), 22.

    Article  Google Scholar 

  129. 129.

    Tao, K., Frisch, J., Rey-Rico, A., et al. (2016). Co-overexpression of TGF-β and SOX9 via rAAV gene transfer modulates the metabolic and chondrogenic activities of human bone marrow-derived mesenchymal stem cells. Stem Cell Research & Therapy, 7(1), 20.

    Article  CAS  Google Scholar 

  130. 130.

    Zanotti, L., Angioni, R., Calì, B., et al. (2016). Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1. Leukemia, 30, 1143–1154.

  131. 131.

    Liu, Z., Wang, C., Wang, X., et al. (2015). Therapeutic effects of transplantation of as-mir-937-expressing mesenchymal stem cells in murine model of alzheimer’s disease. Cellular Physiology and Biochemistry, 37(1), 321–330.

    PubMed  Article  CAS  Google Scholar 

  132. 132.

    Nayak, S., & Herzog, R. W. (2010). Progress and prospects: immune responses to viral vectors. Gene Therapy, 17(3), 295–304.

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Yin, T., He, S., Su, C., et al. (2015). Genetically modified human placenta‑derived mesenchymal stem cells with FGF‑2 and PDGF‑BB enhance neovascularization in a model of hindlimb ischemia. Molecular Medicine Reports, 12(4), 5093–5099.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  134. 134.

    Kanehira, M., Xin, H., Hoshino, K., et al. (2007). Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells. Cancer Gene Therapy, 14(11), 894–903.

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    Gopalakrishnan, A. K., Pandit, H., Metkari, S., et al. (2016). Adenoviral vector encoding soluble Flt-1 engineered human endometrial mesenchymal stem cells effectively regress endometriotic lesions in NOD/SCID mice. Gene Therapy, 23(7), 580–591.

    Article  CAS  Google Scholar 

  136. 136.

    Ryu, C. H., Park, S.-H., Park, S. A., et al. (2011). Gene therapy of intracranial glioma using interleukin 12–secreting human umbilical cord blood–derived mesenchymal stem cells. Human Gene Therapy, 22(6), 733–743.

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Sun, X. L., Xu, Z. M., Ke, Y. Q., et al. (2011). Molecular targeting of malignant glioma cells with an EphA2-specific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells. Cancer Letters, 312(2), 168–177.

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Yang, Y., Nunes, F. A., Berencsi, K., et al. (1994). Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proceedings of the National Academy of Sciences, 91(10), 4407–4411.

  139. 139.

    Treacy, O., Ryan, A. E., Heinzl, T., et al. (2012). Adenoviral transduction of mesenchymal stem cells: in vitro responses and in vivo immune responses after cell transplantation. PLoS One, 7(8), e42662.

  140. 140.

    McCarter, S., Scott, J., Lee, P., et al. (2003). Cotransfection of heme oxygenase-1 prevents the acute inflammation elicited by a second adenovirus. Gene Therapy, 10(19), 1629–1635.

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Alba, R., Bosch, A., & Chillon, M. (2005). Gutless adenovirus: last-generation adenovirus for gene therapy. Gene Therapy, 12, S18-S27.

    Article  CAS  Google Scholar 

  142. 142.

    Lamb, A. (1996). Paramyxoviridae: the virus and their replication. Fields Virology.

  143. 143.

    Knaän-Shanzer, S., van de Watering, M. J., van der Velde, I., et al. (2005). Endowing human adenovirus serotype 5 vectors with fiber domains of species B greatly enhances gene transfer into human mesenchymal stem cells. Stem Cells, 23(10), 1598–1607.

    PubMed  Article  Google Scholar 

  144. 144.

    Zaldumbide, A., Carlotti, F., Gonçalves, M. A., et al. (2012). Adenoviral vectors stimulate glucagon transcription in human mesenchymal stem cells expressing pancreatic transcription factors. PLoS One, 7(10), e48093.

  145. 145.

    Hu, Y. C. (2006). Baculovirus vectors for gene therapy. Advances in Virus Research, 68, 287–320.

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Kost, T. A., Condreay, J. P., & Jarvis, D. L. (2005). Baculovirus as versatile vectors for protein expression in insect and mammalian cells. Nature Biotechnology, 23(5), 567–575.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Merrihew, R. V., Clay, W. C., Condreay, J. P., et al. (2001). Chromosomal integration of transduced recombinant baculovirus DNA in mammalian cells. Journal of Virology, 75(2), 903–909.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Wang, K. C., Wu, J. C., Chung, Y. C., et al. (2005). Baculovirus as a highly efficient gene delivery vector for the expression of hepatitis delta virus antigens in mammalian cells. Biotechnology and Bioengineering, 89(4), 464–473.

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Zeng, J., Du, J., Lin, J., et al. (2009). High-efficiency transient transduction of human embryonic stem cell–derived neurons with baculoviral vectors. Molecular Therapy, 17(9), 1585–1593.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Chen, G. Y., Pang, D. P., Hwang, S. M., et al. (2012). A graphene-based platform for induced pluripotent stem cells culture and differentiation. Biomaterials, 33(2), 418–427.

    PubMed  Article  CAS  Google Scholar 

  151. 151.

    Lee, E. X., Lam, D. H., Wu, C., et al. (2011). Glioma gene therapy using induced pluripotent stem cell derived neural stem cells. Molecular Pharmaceutics, 8(5), 1515–1524.

    CAS  PubMed  Article  Google Scholar 

  152. 152.

    Chen, H. C., Chang, Y. H., Chuang, C. K., et al. (2009). The repair of osteochondral defects using baculovirus-mediated gene transfer with de-differentiated chondrocytes in bioreactor culture. Biomaterials, 30(4), 674–681.

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Sung, L. Y., Lo, W. H., Chiu, H. Y., et al. (2007). Modulation of chondrocyte phenotype via baculovirus-mediated growth factor expression. Biomaterials, 28(23), 3437–3447.

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Bak, X. Y., Dang, H. L., Yang, J., et al. (2011). Human embryonic stem cell-derived mesenchymal stem cells as cellular delivery vehicles for prodrug gene therapy of glioblastoma. Human Gene Therapy, 22(11), 1365–1377.

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Chuang, C. K., Lin, K. J., Lin, C. Y., et al. (2009). Xenotransplantation of human mesenchymal stem cells into immunocompetent rats for calvarial bone repair. Tissue Engineering Part A, 16(2), 479–488.

    Article  CAS  Google Scholar 

  156. 156.

    Lu, C. H., Lin, K. J., Chiu, H. Y., et al. (2012). Improved chondrogenesis and engineered cartilage formation from TGF-β3-expressing adipose-derived stem cells cultured in the rotating-shaft bioreactor. Tissue Engineering Part A, 18(19–20), 2114–2124.

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Liao, J.-C. (2016). Bone marrow mesenchymal stem cells expressing baculovirus-engineered bone morphogenetic protein-7 enhance rabbit posterolateral fusion. International Journal of Molecular Sciences, 17(7), 1073.

  158. 158.

    Liao, J.-C. (2016). Cell therapy using bone marrow-derived stem cell overexpressing BMP-7 for degenerative discs in a rat tail disc model. International Journal of Molecular Sciences, 17(2), 147.

  159. 159.

    Fu, T.-S., Chang, Y.-H., Wong, C.-B., et al. (2015). Mesenchymal stem cells expressing baculovirus-engineered BMP-2 and VEGF enhance posterolateral spine fusion in a rabbit model. The Spine Journal, 15(9), 2036–2044.

    PubMed  Article  Google Scholar 

  160. 160.

    Bak, X., Yang, J., & Wang, S. (2010). Baculovirus-transduced bone marrow mesenchymal stem cells for systemic cancer therapy. Cancer Gene Therapy, 17(10), 721–729.

    CAS  PubMed  Article  Google Scholar 

  161. 161.

    Harrison, R. L., & Jarvis, D. L. (2006). Protein N-glycosylation in the baculovirus–insect cell expression system and engineering of insect cells to produce “Mammalianized” recombinant glycoproteins. Advances in Virus Research, 68, 159–191.

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Manservigi, R., Argnani, R., & Marconi, P. (2010). HSV recombinant vectors for gene therapy. The Open Virology Journal, 4(1), 123–156.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Zhang, G., Kobayashi, T., Kamitani, W., et al. (2003). Borna disease virus phosphoprotein represses p53-mediated transcriptional activity by interference with HMGB1. Journal of Virology, 77(22), 12243–12251.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Leoni, V., Gatta, V., Palladini, A., et al. (2015). Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases. Oncotarget, 6(33), 34774.

    PubMed  PubMed Central  Google Scholar 

  165. 165.

    Breitbach, C. J., Burke, J., Jonker, D., et al. (2011). Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature, 477(7362), 99–102.

    CAS  PubMed  Article  Google Scholar 

  166. 166.

    Heo, J., Reid, T., Ruo, L., et al. (2013). Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nature Medicine, 19(3), 329–336.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Park, B. H., Hwang, T., Liu, T. C., et al. (2008). Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. The Lancet Oncology, 9(6), 533–542.

    CAS  PubMed  Article  Google Scholar 

  168. 168.

    De la Torre, J. (1994). Molecular biology of borna disease virus: prototype of a new group of animal viruses. Journal of Virology, 68(12), 7669.

    PubMed  PubMed Central  Google Scholar 

  169. 169.

    Briese, T., de La Torre, J. C., Lewis, A., et al. (1992). Borna disease virus, a negative-strand RNA virus, transcribes in the nucleus of infected cells. Proceedings of the National Academy of Sciences, 89(23), 11486–11489.

  170. 170.

    Briese, T., Schneemann, A., Lewis, A. J., et al. (1994). Genomic organization of Borna disease virus. Proceedings of the National Academy of Sciences, 91(10), 4362–4366.

  171. 171.

    Schneemann, A., Schneider, P. A., Lamb, R. A., et al. (1995). The remarkable coding strategy of Borna disease virus: a new member of the nonsegmented negative strand RNA viruses. Virology, 210(1), 1–8.

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Ikeda, Y., Makino, A., Matchett, W. E., et al. (2016). A novel intranuclear RNA vector system for long-term stem cell modification. Gene Therapy, 23(3), 256–262.

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    McCarty, D. M. (2008). Self-complementary AAV vectors; advances and applications. Molecular Therapy, 16(10), 1648–1656.

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Gall, J., Kass-Eisler, A., Leinwand, L., et al. (1996). Adenovirus type 5 and 7 capsid chimera: fiber replacement alters receptor tropism without affecting primary immune neutralization epitopes. Journal of Virology, 70(4), 2116–2123.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Ito, H., Goater, J., Tiyapatanaputi, P., et al. (2004). Light-activated gene transduction of recombinant adeno-associated virus in human mesenchymal stem cells. Gene Therapy, 11(1), 34–41.

    CAS  PubMed  Article  Google Scholar 

  176. 176.

    Li, M., Jayandharan, G. R., Li, B., et al. (2010). High-efficiency transduction of fibroblasts and mesenchymal stem cells by tyrosine-mutant AAV2 vectors for their potential use in cellular therapy. Human Gene Therapy, 21(11), 1527–1543.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Pang, Z. P., Yang, N., Vierbuchen, T., et al. (2011). Induction of human neuronal cells by defined transcription factors. Nature, 476(7359), 220–223.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Graf, T., & Enver, T. (2009). Forcing cells to change lineages. Nature, 462(7273), 587–594.

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Lee, A. S., Tang, C., Rao, M. S., et al. (2013). Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nature Medicine, 19(8), 998–1004.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Zhang, Y., Pak, C., Han, Y., et al. (2013). Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron, 78(5), 785–798.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Ramos, C. A., Asgari, Z., Liu, E., et al. (2010). An inducible caspase 9 suicide gene to improve the safety of mesenchymal stromal cell therapies. Stem Cells, 28(6), 1107–1115.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Morris, S. A., Cahan, P., Li, H., et al. (2014). Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell, 158(4), 889–902.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Rombouts, W., & Ploemacher, R. (2003). Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia, 17(1), 160–170.

    CAS  PubMed  Article  Google Scholar 

  184. 184.

    Banfi, A., Muraglia, A., Dozin, B., et al. (2000). Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: implications for their use in cell therapy. Experimental Hematology, 28(6), 707–715.

    CAS  PubMed  Article  Google Scholar 

  185. 185.

    Baron, F., Lechanteur, C., Willems, E., et al. (2010). Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning. Biology of Blood and Marrow Transplantation, 16(6), 838–847.

    PubMed  Article  Google Scholar 

  186. 186.

    Zhou, H., Guo, M., Bian, C., et al. (2010). Efficacy of bone marrow-derived mesenchymal stem cells in the treatment of sclerodermatous chronic graft-versus-host disease: clinical report. Biology of Blood and Marrow Transplantation, 16(3), 403–412.

    CAS  PubMed  Article  Google Scholar 

  187. 187.

    Kuzmina, L. A., Petinati, N. A., Parovichnikova, E. N., et al. (2011). Multipotent mesenchymal stromal cells for the prophylaxis of acute graft-versus-host disease—a phase II study. Stem Cells International, 2012(2012), 8.

    Google Scholar 

  188. 188.

    Miletic, H., Fischer, Y., Litwak, S., et al. (2007). Bystander killing of malignant glioma by bone marrow–derived tumor-infiltrating progenitor cells expressing a suicide gene. Molecular Therapy, 15(7), 1373–1381.

    CAS  PubMed  Article  Google Scholar 

  189. 189.

    Cavarretta, I. T., Altanerova, V., Matuskova, M., et al. (2010). Adipose tissue–derived mesenchymal stem cells expressing prodrug-converting enzyme inhibit human prostate tumor growth. Molecular Therapy, 18(1), 223–231.

    CAS  PubMed  Article  Google Scholar 

  190. 190.

    Van Eekelen, M., Sasportas, L., Kasmieh, R., et al. (2010). Human stem cells expressing novel TSP-1 variant have anti-angiogenic effect on brain tumors. Oncogene, 29(22), 3185–3195.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  191. 191.

    Scholefield, J., & Weinberg, M. S. (2016). The application of CRISPR/Cas9 technologies and therapies in stem cells. Current Stem Cell Reports, 2(2), 95–103.

    CAS  Article  Google Scholar 

  192. 192.

    Ran, F. A., Hsu, P. D., Wright, J., et al. (2013). Genome engineering using the CRISPR-Cas9 system. Nature Protocols, 8(11), 2281–2308.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. 193.

    Ran, F. A., Hsu, P. D., Lin, C.-Y., et al. (2013). Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell, 154(6), 1380–1389.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    Webber, B. R., Osborn, M. J., McElroy, A. N., et al. (2016). CRISPR/Cas9-based genetic correction for recessive dystrophic epidermolysis bullosa. NPJ Regenerative Medicine, 1 , 16014.

  195. 195.

    Cong, L., Ran, F. A., Cox, D., et al. (2013). Multiplex genome engineering using CRISPR/Cas systems. Science, 339(6121), 819–823.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. 196.

    Liu, T., Shen, J. K., Li, Z., et al. (2016). Development and potential applications of CRISPR-Cas9 genome editing technology in sarcoma. Cancer Letters, 373(1), 109–118.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Cho, S. W., Kim, S., Kim, Y., et al. (2014). Analysis of off-target effects of CRISPR/Cas-derived RNA-guided endonucleases and nickases. Genome Research, 24(1), 132–141.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  198. 198.

    Pattanayak, V., Lin, S., Guilinger, J. P., et al. (2013). High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity. Nature Biotechnology, 31(9), 839–843.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Kleinstiver, B. P., Pattanayak, V., Prew, M. S., et al. (2016). High-fidelity CRISPR–Cas9 nucleases with no detectable genome-wide off-target effects. Nature, 529(7587), 490–495.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    Slaymaker, I. M., Gao, L., Zetsche, B., et al. (2016). Rationally engineered Cas9 nucleases with improved specificity. Science, 351(6268), 84–88.

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Albitar, A., Rohani, B., Will, B., et al. (2017). The application of CRISPR/Cas technology to efficiently model complex cancer genomes in stem cells. Journal of Cellular Biochemistry.

  202. 202.

    Blitz, I. L., Biesinger, J., Xie, X., et al. (2013). Biallelic genome modification in F0 Xenopus tropicalis embryos using the CRISPR/Cas system. Genesis, 51(12), 827–834.

  203. 203.

    Jao, L.E., Wente, S. R., & Chen, W. (2013). Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. Proceedings of the National Academy of Sciences, 110(34), 13904–13909.

  204. 204.

    Wang, H., Yang, H., Shivalila, C. S., et al. (2013). One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell, 153(4), 910–918.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. 205.

    Sokolik, C., Liu, Y., Bauer, D., et al. (2015). Transcription factor competition allows embryonic stem cells to distinguish authentic signals from noise. Cell Systems, 1(2), 117–129.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  206. 206.

    Delavar, H. M., Karamzadeh, A., & Pahlavanneshan, S. (2016). Shining light on the sprout of life: optogenetics applications in stem cell research and therapy. The Journal of Membrane Biology, 249(3), 215–220.

    Article  CAS  Google Scholar 

  207. 207.

    Fenno, L. E., Mattis, J., Ramakrishnan, C., et al. (2014). Targeting cells with single vectors using multiple-feature Boolean logic. Nature Methods, 11(7), 763–772.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  208. 208.

    Liu, X., Ramirez, S., Pang, P. T., et al. (2012). Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature, 484(7394), 381–385.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. 209.

    Guru, A., Post, R. J., Ho, Y. Y., et al. (2015). Making sense of optogenetics. International Journal of Neuropsychopharmacology, 18(11), 79.

    Article  CAS  Google Scholar 

  210. 210.

    Pliss, A., Ohulchanskyy, T. Y., Chen, G., et al. (2017). Subcellular optogenetics enacted by targeted nanotransformers of near-infrared light. ACS Photonics, 4(4), 806–814.

    CAS  Article  Google Scholar 

  211. 211.

    Meyer, U. A. (2002). Introduction to pharmacogenomics: promises, opportunities, and limitations. Pharmacogenomics: The search for individualized therapies, pp. 1–8.

  212. 212.

    Langman, L. J., Nesher, L., Shah, D. P., et al. (2016). Challenges in determining genotypes for pharmacogenetics in allogeneic hematopoietic cell transplant recipients. The Journal of Molecular Diagnostics, 18(5), 638–642.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  213. 213.

    Licinio, J., & Wong, M. L. (2009). Pharmacogenomics: The search for individualized therapies. Wiley.

  214. 214.

    Al-Mahayri, Z. N., & Patrinos, G. P., & Ali, R. (2017). Pharmacogenomics in pediatric acute lymphoblastic leukemia: promises and limitations. The Journal of Molecular Diagnostics, 18(7), 687–699.

  215. 215.

    Van Hassselt, J. C., & Iyengar, R. (2017). Systems pharmacology-based identification of pharmacogenomic determinants of adverse drug reactions using human iPSC-derived cell lines. Current Opinion in Systems Biology, 4, 9–15.

    Article  Google Scholar 

Download references

Acknowledgements

Authors acknowledge Dr. T, Ramakrishna for critical reading of the manuscript and suggestions. Kiran Kumar acknowledge CSIR network project mIND (BSC-0115) for financial assistance. Ch. Mohan Rao acknowledges the Department of Science and Technology, Government of India for the Sir JC Bose National Fellowship.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Kiran Kumar Bokara.

Ethics declarations

Conflict of Interest

The authors confirm that this article content has no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Oggu, G.S., Sasikumar, S., Reddy, N. et al. Gene Delivery Approaches for Mesenchymal Stem Cell Therapy: Strategies to Increase Efficiency and Specificity. Stem Cell Rev and Rep 13, 725–740 (2017). https://doi.org/10.1007/s12015-017-9760-2

Download citation

Keywords

  • Mesenchymal stem cells
  • Viral vectors
  • Gene delivery
  • Stem cell applications
  • CRISPR/Cas
  • Optogenetics
  • Pharmacogenomics