Self-Organized Cerebellar Tissue from Human Pluripotent Stem Cells and Disease Modeling with Patient-Derived iPSCs
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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.
KeywordsPurkinje cells Pluripotent stem cells Spinocerebellar ataxia Disease modeling Brain organoid Self-organization Cerebellar development
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.
Compliance with Ethical Standards
The author declares that she has no competing interests.
- 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. https://doi.org/10.1242/dmm.010900.CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1371/journal.pone.0101718.CrossRefPubMedPubMedCentralGoogle Scholar
- 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. https://doi.org/10.1089/scd.2017.0085.CrossRefPubMedPubMedCentralGoogle Scholar
- 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. https://doi.org/10.1186/s13041-015-0180-4.CrossRefPubMedPubMedCentralGoogle Scholar