Self-Organized Cerebellar Tissue from Human Pluripotent Stem Cells and Disease Modeling with Patient-Derived iPSCs


Recent advances in the techniques that differentiate induced pluripotent stem cells (iPSCs) into specific types of cells enabled us to establish in vitro cell-based models as a platform for drug discovery. iPSC-derived disease models are advantageous to generation of a large number of cells required for high-throughput screening. Furthermore, disease-relevant cells differentiated from patient-derived iPSCs are expected to recapitulate the disorder-specific pathogenesis and physiology in vitro. Such disease-relevant cells will be useful for developing effective therapies. We demonstrated that cerebellar tissues are generated from human PSCs (hPSCs) in 3D culture systems that recapitulate the in vivo microenvironments associated with the isthmic organizer. Recently, we have succeeded in generation of spinocerebellar ataxia (SCA) patient-derived Purkinje cells by combining the iPSC technology and the self-organizing stem cell 3D culture technology. We demonstrated that SCA6-derived Purkinje cells exhibit vulnerability to triiodothyronine depletion, which is suppressed by treatment with thyrotropin-releasing hormone and Riluzole. We further discuss applications of patient-specific iPSCs to intractable cerebellar disease.

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  1. 1.

    Muguruma K, Sasai Y. In vitro recapitulation of neural development using embryonic stem cells: from neurogenesis to histogenesis. Develop Growth Differ. 2012;54(3):349–57.

    CAS  Article  Google Scholar 

  2. 2.

    Sasai Y. Next-generation regenerative medicine: organogenesis from stem cells in 3D culture. Cell Stem Cell. 2013;12(5):520–30.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Muguruma K, Nishiyama A, Ono Y, Miyawaki H, Mizuhara E, Hori S, et al. Ontogeny-recapitulating generation and tissue integration of ES cell-derived Purkinje cells. Nature Neurosci. 2010;13(10):1171–80.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Muguruma K, Nishiyama A, Kawakami H, Hashimoto K, Sasai Y. Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep. 2015;10(4):537–50.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Joyner AL, Liu A, Millet S. Otx2, Gbx2 and Fgf8 interact to position and maintain a mid-hindbrain organizer. Curr Opin Cell Biol. 2000;12(6):736–41.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Wurst W, Bally-Cuif L. Neural plate patterning: upstream and downstream of the isthmic organizer. Nature. Rev Neurosci. 2001;2(2):99–108.

    CAS  Article  Google Scholar 

  7. 7.

    Martinez S, Andreu A, Mecklenburg N, Echevarria D. Cellular and molecular basis of cerebellar development. Front Neuroanat. 2013;7:1–12.

    Article  Google Scholar 

  8. 8.

    Marzban H, Del Bigio MR, Alizadeh J, Ghavami S, Zachariah RM, Rastegar M. Cellular commitment in the developing cerebellum. Front Cell Neurosci. 2015;18:450.

    Google Scholar 

  9. 9.

    Carletti B, Rossi F. Neurogenesis in the cerebellum. Neuroscientist. 2008;14(1):91–100.

    Article  PubMed  Google Scholar 

  10. 10.

    Leto K, Arancillo M, Becker EBE, Buffo A, Chiang C, Ding B, et al. Consensus paper: cerebellar development. Cerebellum. 2016;15(6):789–828.

    Article  PubMed  Google Scholar 

  11. 11.

    Watson LM, Wong MMK, Becker EBE. Induced pluripotent stem cell technology for modeling and therapy of cerebellar ataxia. Open Biol. 2015;5(7):150056.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Rüb U, Schöls L, Paulson H, Auburger G, Kermer P, Jen JC, et al. Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1,2,3,6 and 7. Prog Neurobiol. 2013;104:38–66.

    Article  PubMed  Google Scholar 

  13. 13.

    Ishida Y, Kawakami H, Kitajima H, Nishiyama A, Sasai Y, Inoue H, et al. Vulnerability of Purkinje cells generated from spinocerebellar ataxia type 6 patient-derived iPSCs. Cell Rep. 2016;17(6):1482–90.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Du X, Wang J, Zhu H, Rinaldo L, Lamar KM, Palmenberg AC, et al. Second cistron in CACNA1A gene incodes a transcription factor mediating cerebellar development and SCA6. Cell. 2013;154(1):118–33.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Kordasiewicz HB, Thompson RM, Clark HB, Gomez CM. C-termini of P/Q-type Ca2+ channel α1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Hum Mol Genet. 2006;15(10):1587–99.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Shi Y, Inoue H, Wu JC, Yamanaka S. Induced pluripotent stem cell technology: a decade of progress. Nature Rev Drug Discov. 2017;16:115–30.

    CAS  Article  Google Scholar 

  17. 17.

    Ardhanareeswaran K, Mariani J, Coppola G, Abyzov A, Vaccarino FM. Human induced pluripotent stem cells for modeling neurodevelopmental disorders. Nature Rev Neurol. 2017;13(5):265–78.

    Article  Google Scholar 

  18. 18.

    Ku S, Soragni E, Campau E, Thomas EA, Altun G, Laurent LC, et al. Friedreich’s ataxia induced pluripotent stem cells model intergenerational GAA∙TTC triplet repeat instability. Cell Stem Cell. 2010;7(5):631–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, Poppe D, et al. Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature. 2011;480(7378):543–6.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Hick A, Wattenhofer-Donze M, Chintawar S, Tropel P, Simard JP, Vaucamps N, et al. Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich’s ataxia. Dis Model Mech. 2013;6(3):608–21.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Bird MJ, Needham K, Frazier AE, van Rooijen J, Leung J, Hough S, et al. Functional characterization of Friedreich ataxia iPS derived neuronal progenitors and their integration on the adult brain. PLoS One. 2014;9(7):e101718.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Bavassano C, Eigentler A, Stanika R, Obermair GJ, Boesch S, Dechant G, et al. Bicistronic CACNA1A gene expression in neurons derived from spinocerebellar ataxia type 6 patient-induced pluripotent stem cells. Stem Cells Dev. 2017;26(22):1612–25.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Klockgether T. Update on degenerative ataxias. Curr Opin Neurol. 2011;24(4):339–245.

    Article  PubMed  Google Scholar 

  24. 24.

    Manto M, Marmolino D. Cerebellar ataxias. Curr Opin Neurol. 2009;22(4):419–29.

    Article  PubMed  Google Scholar 

  25. 25.

    Morino H, Matsuda Y, Muguruma K, Miyamoto R, Ohsawa R, Ohtake T, et al. A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Molecular Brain. 2015;8(1):89.

    Article  PubMed  PubMed Central  Google Scholar 

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This work was supported by grant-in-aid from Ministry of Health, Labour and Welfare, grant-in-aid for Scientific Research (C) from Japan Society for the Promotion of Science (JSPS), and the Core Program for Disease Modeling using iPS Cells from JST and AMED.

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Correspondence to Keiko Muguruma.

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Muguruma, K. Self-Organized Cerebellar Tissue from Human Pluripotent Stem Cells and Disease Modeling with Patient-Derived iPSCs. Cerebellum 17, 37–41 (2018).

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  • Purkinje cells
  • Pluripotent stem cells
  • Spinocerebellar ataxia
  • Disease modeling
  • Brain organoid
  • Self-organization
  • Cerebellar development