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The Cerebellum

, Volume 13, Issue 3, pp 323–330 | Cite as

Mesenchymal Stem Cells Ameliorate Cerebellar Pathology in a Mouse Model of Spinocerebellar Ataxia Type 1

  • Serina Matsuura
  • Anton N. Shuvaev
  • Akira Iizuka
  • Kazuhiro Nakamura
  • Hirokazu HiraiEmail author
Original Paper

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disorder caused by the expansion of a polyglutamine tract in the ataxin-1 protein. To date, no fundamental treatments for SCA1 have been elucidated. However, some studies have shown that mesenchymal stem cells (MSCs) are partially effective in other genetic mouse models of cerebellar ataxia. In this study, we tested the efficacy of the intrathecal injection of MSCs in the treatment of SCA1 in transgenic (SCA1-Tg) mice. We found that intrathecal injection of only 3 × 103 MSCs greatly mitigated the cerebellar neuronal disorganization observed in SCA1 transgenic mice (SCA1-Tg mice). Although the Purkinje cells (PCs) of 24-week-old nontreated SCA1-Tg mice displayed a multilayer arrangement, SCA1-Tg mice at a similar age injected with MSCs displayed monolayer PCs. Furthermore, intrathecal injection of MSCs suppressed the atrophy of PC dendrites in SCA1-Tg mice. Finally, behavioral tests demonstrated that MSCs normalized deficits in motor coordination in SCA1-Tg mice. Future studies should be performed to develop optimal protocols for intrathecal transplantation of MSCs in SCA1 model primates with the aim of developing applications for SCA1 patients.

Keywords

Mesenchymal stem cells Motor coordination Mouse Purkinje cells Spinocerebellar ataxia type 1 Neurodegenerative disease Ataxia 

Notes

Acknowledgments

This work was supported by the Funding Program for Next Generation World-Leading Researchers (LS021) (to H. Hirai) and by grants in aid from the Research Committee for Ataxic Disease, the Ministry of Health, Labour and Welfare of Japan (to K. Nakamura).

Conflicts of interest

There are no potential conflicts of interest in the content of this paper.

References

  1. 1.
    Matilla-Dueñas A, Goold R, Giunti P. Clinical, genetic, molecular, and pathophysiological insights into spinocerebellar ataxia type 1. Cerebellum. 2008;7:106–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Robitaille Y, Schut L, Kish SJ. Structural and immunocytochemical features of olivopontocerebellar atrophy caused by the spinocerebellar ataxia type 1 (SCA-1) mutation define a unique phenotype. Acta Neuropathol. 1995;90:572–81.PubMedCrossRefGoogle Scholar
  3. 3.
    Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet. 1983;1:1151–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Burright NE, Clark BH, Servadio A, Matilla T, Feddersen MR, Yunis SW, et al. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell. 1995;82:937–48.PubMedCrossRefGoogle Scholar
  5. 5.
    Clark HB, Burright EN, Yunis WS, Larson S, Wilcox C, Hartman B, et al. Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations. J Neurosci. 1997;17:7385–95.PubMedGoogle Scholar
  6. 6.
    Xia H, Mao Q, Eliason LS, Harper QS, Martins HI, Orr TH, et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med. 2004;10:816–20.PubMedCrossRefGoogle Scholar
  7. 7.
    Lee Y, Samaco CR, Gatche RJ, Thaller C, Orr TH, Zoghbi YH. miR-19, miR-101 and miR-130 co-regulate ATXN1 levels to potentially modulate SCA1 pathogenesis. Nat Neurosci. 2008;11:1137–9.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Chintawar S, Hourez R, Ravella A, Gall D, Orduz D, Rai M, et al. Grafting neural precursor cells promotes functional recovery in an SCA1 mouse model. Neurobiol Dis. 2009;29:13126–35.Google Scholar
  9. 9.
    Mazzini L, Ferrero I, Luparello V, Rustichelli D, Gunetti M, Mareschi K, et al. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a phase I clinical trial. Exp Neurol. 2009;223:229–37.PubMedCrossRefGoogle Scholar
  10. 10.
    Pittenger FM, Mackay MA, Beck CS, Jaiswal KR, Douglas R, Mosca DJ, et al. Multilineage potential of adult human mesenchymal stem cells. Sci. 2001;276:143–7.Google Scholar
  11. 11.
    Woodbury D, Reynolds K, Black BI. Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J Neurosci Res. 2002;69:908–17.PubMedCrossRefGoogle Scholar
  12. 12.
    Lagasse E, Connors H, Dhalimy AM, Reitsma M, Dohse M, Osborne L, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000;6:1229–34.PubMedCrossRefGoogle Scholar
  13. 13.
    Lee KO, Kuo KT, Chen MW, Lee DK, Hsieh LS, Chen HT. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood. 2004;103:1669–75.PubMedCrossRefGoogle Scholar
  14. 14.
    Baddoo M, Hill K, Wilkinson R, Gaupp D, Hughes C, Kopen CG, et al. Characterization of mesenchymal stem cells isolated from murine bone marrow by negative selection. J Biochem. 2003;89:1235–49.Google Scholar
  15. 15.
    Gimble MJ, Guilak F. Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy. 2003;5:362–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Peneva M, Mitev V, Ishketiev N. Isolation of mesenchymal stem cells from the pulp of deciduous teeth. J IMAB. 2008;2:84–7.Google Scholar
  17. 17.
    Chang KY, Chen HM, Chiang HY, Chen FY, Ma HW, Tseng YC, et al. Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. J Biomed Sci. 2011;18:54.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Jones J, Merchán JJ, Bueno C, Pastor D, León VM, Martínez S. Mesenchymal stem cells rescue Purkinje cells and improve motor functions in a mouse model of cerebellar ataxia. Neurobiol Dis. 2010;40:415–23.PubMedCrossRefGoogle Scholar
  19. 19.
    Shuvaev NA, Horiuchi H, Seki T, Goenawan H, Irie T, Iizuka A, et al. Mutant PKCγ in spinocerebellar ataxia type 14 disrupts synapse elimination and long-term depression in Purkinje cells in vivo. J Neurosci. 2011;31(40):14324–34.PubMedCrossRefGoogle Scholar
  20. 20.
    Iwamoto N, Watanabe A, Yamamoto M, Miyake N, Kurai T, Teramoto A, et al. Global diffuse distribution in the brain and efficient gene delivery to the dorsal root ganglia by intrathecal injection of adeno-associated viral vector serotype 1. J Gene Med. 2009;11:498–505.PubMedCrossRefGoogle Scholar
  21. 21.
    Bonab MM, Sahraian AM, Aghsaie A, Karvigh AS, Hosseinian MS, Nikbin B, et al. Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study. Curr Stem Cell Res Ther. 2012;7:407–14.PubMedCrossRefGoogle Scholar
  22. 22.
    Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta AJ. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med. 2010;5:933–46.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Meyerrose T, Olson S, Pontow S, Kalomoiris S, Jung Y, Annett G, et al. Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. Adv Drug Deliv Rev. 2010;62:1167–74.PubMedCrossRefGoogle Scholar
  24. 24.
    Olson DS, Pollock K, Kambal A, Cary W, Mitchell MG, Tempkin J, et al. Genetically engineered mesenchymal stem cells as a proposed therapeutic for Huntington’s disease. Mol Neurobiol. 2012;45:87–98.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Liu J, Han D, Wang Z, Xue M, Zhu L, Yan H, et al. Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells. Cytotherapy. 2013;15:185–91.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Serina Matsuura
    • 1
  • Anton N. Shuvaev
    • 1
  • Akira Iizuka
    • 1
  • Kazuhiro Nakamura
    • 1
  • Hirokazu Hirai
    • 1
    Email author
  1. 1.Department of NeurophysiologyGunma University Graduate School of MedicineMaebashiJapan

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