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ALS disrupts spinal motor neuron maturation and aging pathways within gene co-expression networks

Nature Neuroscience volume 19, pages 12561267 (2016) | Download Citation

Abstract

Modeling amyotrophic lateral sclerosis (ALS) with human induced pluripotent stem cells (iPSCs) aims to reenact embryogenesis, maturation and aging of spinal motor neurons (spMNs) in vitro. As the maturity of spMNs grown in vitro compared to spMNs in vivo remains largely unaddressed, it is unclear to what extent this in vitro system captures critical aspects of spMN development and molecular signatures associated with ALS. Here, we compared transcriptomes among iPSC-derived spMNs, fetal spinal tissues and adult spinal tissues. This approach produced a maturation scale revealing that iPSC-derived spMNs were more similar to fetal spinal tissue than to adult spMNs. Additionally, we resolved gene networks and pathways associated with spMN maturation and aging. These networks enriched for pathogenic familial ALS genetic variants and were disrupted in sporadic ALS spMNs. Altogether, our findings suggest that developing strategies to further mature and age iPSC-derived spMNs will provide more effective iPSC models of ALS pathology.

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Acknowledgements

The authors gratefully acknowledge B. Shelley, L. Garcia and L. Ornelas for assistance with experiments and reagent organization; B. Berman and D. Rushton for statistical and programming advice; and B. Berman, V. Mattis and S. Svendsen for critical reading and comments on the manuscript. This work was supported by the following grants: NIH/NINDS (U54NS091046-01) (C.N.S.) and the ALS Association (R.H. and C.N.S.). Project ALS supported work done by H.W. and M.W.A.

Author information

Affiliations

  1. Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Ritchie Ho
    • , Samuel Sances
    • , Genevieve Gowing
    • , Jacqueline G O'Rourke
    • , Anais Sahabian
    • , Robert H Baloh
    • , Dhruv Sareen
    •  & Clive N Svendsen
  2. Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.

    • Mackenzie Weygandt Amoroso
  3. Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, New York, USA.

    • Hynek Wichterle
  4. Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.

    • Hynek Wichterle
  5. Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Robert H Baloh
  6. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Dhruv Sareen
    •  & Clive N Svendsen

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Contributions

Conceptualization: R.H. and C.N.S.; methodology: R.H.; software: R.H.; formal analysis: R.H.; investigation: R.H., S.S., G.G., M.W.A., J.G.O'R., A.S., D.S. and C.N.S.; resources: H.W., R.H.B., D.S. and C.N.S.; data curation: R.H.; writing original draft: R.H. and C.N.S.; review and editing: R.H., S.S., M.W.A. and C.N.S.; visualization: R.H.; supervision: C.N.S.; funding acquisition: C.N.S.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Clive N Svendsen.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6.

  2. 2.

    Supplementary Methods Checklist

Excel files

  1. 1.

    Supplementary Table 1

    Summary of RNA expression profile data used in this study, Related to all figures.

  2. 2.

    Supplementary Table 2

    Gene expression analysis of Affymetrix Human Genome U133 Plus 2.0 Array samples used for hierarchical clustering, PCA and WGCNA, Related to all figures.

  3. 3.

    Supplementary Table 3

    Gene expression of multiple microarray samples used for Pearson correlation, PCA, and ROC analysis, Related to Figure 3 and Supplementary Figure 3.

  4. 4.

    Supplementary Table 4

    Gene expression of samples from mtSOD1 and control spMNs [9] and iMNs [20] used for MA plots, Related to Figure 4.

  5. 5.

    Supplementary Table 5

    Gene expression analysis of sALS and control spMNs [21] used for hierarchical clustering, PCA and WGCNA, Related to Figures 5, 6, Supplementary Figures 5, and 6.

  6. 6.

    Supplementary Table 6

    Gene property analysis of Age, spMN maturation, and sALS modules, Related to Figure 6.

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DOI

https://doi.org/10.1038/nn.4345

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