Article

Cerebral organoids model human brain development and microcephaly

  • Nature volume 501, pages 373379 (19 September 2013)
  • doi:10.1038/nature12517
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Abstract

The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue.

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Acknowledgements

We are grateful to members of the Knoblich laboratory for technical expertise and feedback, A. Peer, P. Moeseneder and N. Corsini for experimental support and M. Repic for help with establishing organoid electroporations. We also thank the Stem Cell and BioOptics core facilities of IMBA/IMP for technical support. We would especially like to thank the patients and their families for participating in this study. We would also like to thank S. McGurk for providing control MRI images. M.A.L. received funding from an EMBO post-doctoral fellowship and a Helen Hay Whitney post-doctoral fellowship. Work in A.P.J.’s laboratory is supported by the Medical Research Council, a starter grant from the European Research Council (ERC) and the Lister Institute for Preventative Medicine. This research was also supported in part by Wellcome Trust grant WT098051. Work in J.A.K.’s laboratory is supported by the Austrian Academy of Sciences, the Austrian Science Fund (FWF) (projects Z153-B09 and I552-B19) and an advanced grant from ERC.

Author information

Affiliations

  1. Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna 1030, Austria

    • Madeline A. Lancaster
    • , Magdalena Renner
    • , Daniel Wenzel
    • , Josef M. Penninger
    •  & Juergen A. Knoblich
  2. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK

    • Carol-Anne Martin
    • , Louise S. Bicknell
    •  & Andrew P. Jackson
  3. Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK

    • Matthew E. Hurles
  4. Department of Clinical Genetics, St. George’s University, London SW17 0RE, UK

    • Tessa Homfray

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Contributions

M.A.L. and J.A.K. conceived the project and experimental design and wrote the manuscript. M.A.L. performed experiments and analysed data. M.R., C.-A.M. and D.W. performed experiments and analysed data under the supervision of J.A.K., J.M.P. and A.P.J. L.S.B., M.E.H. and T.H. performed patient diagnosis and provided MRIs coordinated by A.P.J. J.A.K. directed and supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Juergen A. Knoblich.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Text.

Videos

  1. 1.

    Interkinetic nuclear migration in cerebral organoids

    Live imaging of GFP electroporated organoid revealing movement of nuclei along apical and basal processes of RG. Arrow marks one RG in particular with clear IKNM. Time shown in hrs:min.

  2. 2.

    Calcium surges in neurons of cerebral organoids

    Live imaging of Fluo-4 signal in a human cerebral organoid revealing spontaneous calcium surges in individual neurons (arrows). Time shown in min:sec.

  3. 3.

    False colour heat map of spontaneous neural activity

    False colour heat map of a zoomed in region of Supplemental Video 2 showing spontaneous calcium surges. Time shown in min:sec.

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