Advertisement

Science China Life Sciences

, Volume 59, Issue 9, pp 950–957 | Cite as

Treatment of multiple sclerosis by transplantation of neural stem cells derived from induced pluripotent stem cells

  • Chao Zhang
  • Jiani Cao
  • Xiaoyan Li
  • Haoyu Xu
  • Weixu Wang
  • Libin Wang
  • Xiaoyang Zhao
  • Wei Li
  • Jianwei Jiao
  • Baoyang Hu
  • Qi Zhou
  • Tongbiao Zhao
Open Access
Research Paper

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), with focal T lymphocytic infiltration and damage of myelin and axons. The underlying mechanism of pathogenesis remains unclear and there are currently no effective treatments. The development of neural stem cell (NSC) transplantation provides a promising strategy to treat neurodegenerative disease. However, the limited availability of NSCs prevents their application in neural disease therapy. In this study, we generated NSCs from induced pluripotent stem cells (iPSCs) and transplanted these cells into mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. The results showed that transplantation of iPSC-derived NSCs dramatically reduced T cell infiltration and ameliorated white matter damage in the treated EAE mice. Correspondingly, the disease symptom score was greatly decreased, and motor ability was dramatically rescued in the iPSC-NSC-treated EAE mice, indicating the effectiveness of using iPSC-NSCs to treat MS. Our study provides pre-clinical evidence to support the feasibility of treating MS by transplantation of iPSC-derived NSCs.

Keywords

induced pluripotent stem cell multiple sclerosis neural stem cell regenerative medicine transplantation 

References

  1. Ager, R.R., Davis, J.L., Agazaryan, A., Benavente, F., Poon, W.W., La- Ferla, F.M., and Blurton-Jones, M. (2015). Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer’s disease and neuronal loss. Hippocampus 25, 813–826.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Araki, R., Uda, M., Hoki, Y., Sunayama, M., Nakamura, M., Ando, S., Sugiura, M., Ideno, H., Shimada, A., Nifuji, A., and Abe, M. (2013). Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 494, 100–104.CrossRefPubMedGoogle Scholar
  3. Arima, Y., Harada, M., Kamimura, D., Park, J.H., Kawano, F., Yull, F.E., Kawamoto, T., Iwakura, Y., Betz, U.A.K. and Abe, M. (2013). Negligible immunogenicity of terminally differendefines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell 148, 447–457.CrossRefGoogle Scholar
  4. Bai, L., Hecker, J., Kerstetter, A., and Miller, R.H. (2013). Myelin repair and functional recovery mediated by neural cell transplantation in a mouse model of multiple sclerosis. Neurosci Bull 29, 239–250.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Beare, J., E., Morehouse, J., R., DeVries, W., H., Enzmann, G., U., Burke, D., A., Magnuson, D., S.K., and Whittemore, S., R. (2009). Gait analysis in normal and spinal cotused mice using the treadscan system. J Neurotrauma 11, 2045–2056.CrossRefGoogle Scholar
  6. Ben-Hur, T., Idelson, M., Khaner, H., Pera, M., Reinhartz, E., Itzik, A., and Reubinoff, B.E. (2004). Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats. Stem Cells 22, 1246–1255.CrossRefPubMedGoogle Scholar
  7. Cao, J., Li, X., Lu, X., Zhang, C., Yu, H., and Zhao, T. (2014). Cells derived from iPSC can be immunogenic—yes or no? Protein Cell 5, 1–3.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Compston, A., and Coles, A. (2008). Multiple sclerosis. Lancet 372, 1502–1517.CrossRefPubMedGoogle Scholar
  9. Constantinescu, C.S., Farooqi, N., O’Brien, K., and Gran, B. (2011). Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 164, 1079–1106.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Crusio, W., E. (2001). Genetic dissection of mouse exploratory behaviour. Behav Brain Res 125, 127–132.CrossRefPubMedGoogle Scholar
  11. Cundiff, P.E., and Anderson, S.A. (2011). Impact of induced pluripotent stem cells on the study of central nervous system disease. Curr Opin Genet Dev 21, 354–361.CrossRefPubMedPubMedCentralGoogle Scholar
  12. de Almeida, P.E., Meyer, E.H., Kooreman, N.G., Diecke, S., Dey, D., Sanchez-Freire, V., Hu, S., Ebert, A., Odegaard, J., Mordwinkin, N.M., Brouwer, T.P., Lo, D., Montoro, D.T., Longaker, M.T., Negrin, R.S., and Wu, J.C. (2014). Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance. Nat Commun 5, 3903.PubMedPubMedCentralGoogle Scholar
  13. Durnaoglu, S., Genc, S., and Genc, K. (2011). Patient-specific pluripotent stem cells in neurological diseases. Stem Cells Int 2011, 212487.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Einstein, O., Karussis, D., Grigoriadis, N., Mizrachi-Kol, R., Reinhartz, E., Abramsky, O., and Ben-Hur, T. (2003). Intraventricular transplantation of neural precursor cell spheres attenuates acute experimental allergic encephalomyelitis. Mol Cell Neurosci 24, 1074–1082.CrossRefPubMedGoogle Scholar
  15. Fassas, A., Anagnostopoulos, A., and Tsompanakou, A. (1997). Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant 20, 631–638.CrossRefPubMedGoogle Scholar
  16. Fisher-Shoval, Y., Barhum, Y., Sadan, O., Yust-Katz, S., Ben-Zur, T., Lev, N., Benkler, C., Hod, M., Melamed, E., and Offen, D. (2012). Transplantation of placenta-derived mesenchymal stem cells in the EAE mouse model of MS.J Mol Neurosci 48, 176–184.Google Scholar
  17. Harris, V.K., Yan, Q.J., Vyshkina, T., Sahabi, S., Liu, X., and Sadiq, S.A. (2012). Clinical and pathological effects of intrathecal injection of mesenchymal stem cell-derived neural progenitors in an experimental model of multiple sclerosis. J Neurol Sci 313, 167–177.CrossRefPubMedGoogle Scholar
  18. Huang, S., and Fu, X. (2014). Stem cell therapies and regenerative medicine in China. Sci China Life Sci 57, 157–161.CrossRefPubMedGoogle Scholar
  19. Israel, M.A., Yuan, S.H., Bardy, C., Reyna, S.M., Mu, Y., Herrera, C., Hefferan, M.P., Van Gorp, S., Nazor, K.L., Boscolo, F.S., Carson, C.T., Laurent, L.C., Marsala, M., Gage, F.H., Remes, A.M., Koo, E.H., and Goldstein, L.S. (2012). Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216–220.PubMedPubMedCentralGoogle Scholar
  20. Jelinek, G.A., Weiland, T.J., Hadgkiss, E.J., Marck, C.H., Pereira, N., and van der Meer, D.M. (2015). Medication use in a large international sample of people with multiple sclerosis: associations with quality of life, relapse rate and disability. Neurol Res 37, 662–673.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kim, H., Walczak, P., Kerr, C., Galpoththawela, C., Gilad, A.A., Muja, N., and Bulte, J.W. (2012). Immunomodulation by transplanted human embryonic stem cell-derived oligodendroglial progenitors in experimental autoimmune encephalomyelitis. Stem Cells 30, 2820–2829.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kim, J.H., Auerbach, J.M., Rodriguez-Gomez, J.A., Velasco, I., Gavin, D., Lumelsky, N., Lee, S.H., Nguyen, J., Sanchez-Pernaute, R., Bankiewicz, K., and McKay, R. (2002). Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 418, 50–56.CrossRefPubMedGoogle Scholar
  23. Kleinschmidt-DeMasters, B.K., and Tyler K. L. (2005). Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353, 369–374.CrossRefPubMedGoogle Scholar
  24. Lajimi, A.A., Hagh, M.F., Saki, N., Mortaz, E., Soleimani, M., and Rahim, F. (2012). Feasibility of cell therapy in multiple sclerosis: a systematic review of 83 studies. Int J Hematol Oncol Stem Cell Res 7, 15–33.Google Scholar
  25. Lee, S.T., Chu, K., Park, J.E., Lee, K., Kang, L., Kim, S.U., and Kim, M. (2005). Intravenous administration of human neural stem cells induces functional recovery in Huntington’s disease rat model. Neurosci Res 52, 243–249.CrossRefPubMedGoogle Scholar
  26. Liu, K., Song, Y., Yu, H., and Zhao, T. (2014). Understanding the roadmaps to induced pluripotency. Cell Death Dis 5, e1232.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lu, X., and Zhao, T. (2013). Clinical therapy using iPSCs: hopes and challenges. Genomics Proteomics Bioinformatics 11, 294–298.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Okabe, S., Nilsson, K., F., Spiro, A. C., Segal, M., and McKay, R., D.G (1996). Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev 59, 89–102.CrossRefPubMedGoogle Scholar
  29. Pluchino, S., Gritti, A., Blezer, E., Amadio, S., Brambilla, E., Borsellino, G., Cossetti, C., Del Carro, U., Comi, G., Hart, B., Vescovi, A., and Martino, G. (2009). Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol 66, 343–354.CrossRefPubMedGoogle Scholar
  30. Pluchino, S., and Martino, G. (2008). The therapeutic plasticity of neural stem/precursor cells in multiple sclerosis. J Neurol Sci 265, 105–110.CrossRefPubMedGoogle Scholar
  31. Pluchino, S., Quattrini, A., Brambilla, E., Gritti, A., Salani, G., Dina, G., Galli, R., Del Carro, U., Amadio, S., and Bergami, A. (2003). Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422, 688–694.CrossRefPubMedGoogle Scholar
  32. Redmond, D.E., Bjugstad, K.B., Teng, Y.D., Ourednik, V., Ourednik, J., Wakeman, D.R., Parsons, X.H., Gonzalez, R., Blanchard, B.C., Kim, S.U., Gu, Z., Lipton, S.A., Markakis, E.A., Roth, R.H., Elsworth, J.D., Sladek, J.R., Sidman, R.L., and Snyder, E.Y. (2007). Behavioral improvement in a primate Parkinson’s model is associated with multiple homeostatic effects of human neural stem cells. Proc Natl Acad Sci USA 104, 12175–12180.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676.CrossRefPubMedGoogle Scholar
  34. Viglietta, V., Baecher-Allan, C., Weiner, H.L., and Hafler, D.A. (2004). Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199, 971–979.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Wu, S., Li, K., Yan, Y., Gran, B., Han, Y., Zhou, F., Guan, Y.T., Rostami, A., and Zhang, G.X. (2013). Intranasal delivery of neural stem cells: a CNS-specific, non-invasive cell-based therapy for experimental autoimmune encephalomyelitis. J Clin Cell Immunol 4, doi: 10.4172/2155-9899.1000142.Google Scholar
  36. Ying, Q.L., Stavridis, M., Griffiths, D., Li, M., and Smith, A. (2003). Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat Biotechnol 21, 183–186.CrossRefPubMedGoogle Scholar
  37. Zhao, T., Zhang, Z.N., Rong, Z., and Xu, Y. (2011). Immunogenicity of induced pluripotent stem cells. Nature 474, 212–215.CrossRefPubMedGoogle Scholar
  38. Zhao, T., Zhang, Z.N., Westenskow, P.D., Todorova, D., Hu, Z., Lin, T., Rong, Z., Kim, J., He, J., Wang, M., Clegg, D.O., Yang, Y.G., Zhang, K., Friedlander, M., and Xu, Y. (2015). Humanized mice reveal differential immunogenicity of cells derived from autologous induced pluripotent stem cells. Cell Stem Cell 17, 353–359.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2016

Authors and Affiliations

  • Chao Zhang
    • 1
    • 2
  • Jiani Cao
    • 1
  • Xiaoyan Li
    • 1
  • Haoyu Xu
    • 1
    • 2
  • Weixu Wang
    • 1
  • Libin Wang
    • 1
    • 2
  • Xiaoyang Zhao
    • 1
  • Wei Li
    • 1
  • Jianwei Jiao
    • 1
  • Baoyang Hu
    • 1
  • Qi Zhou
    • 1
  • Tongbiao Zhao
    • 1
  1. 1.State Key Laboratory of Stem Cell and Reproductive Biology, Institute of ZoologyChinese Academy of SciencesBeijingChina
  2. 2.Graduate University of Chinese Academy of SciencesBeijingChina

Personalised recommendations