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Assembly of functionally integrated human forebrain spheroids

Author

Listed:
  • Fikri Birey

    (Center for Sleep Sciences and Medicine, Stanford University School of Medicine)

  • Jimena Andersen

    (Center for Sleep Sciences and Medicine, Stanford University School of Medicine)

  • Christopher D. Makinson

    (Stanford University School of Medicine)

  • Saiful Islam

    (Stanford University School of Medicine)

  • Wu Wei

    (Stanford University School of Medicine
    Stanford Genome Technology Center, Stanford University)

  • Nina Huber

    (Center for Sleep Sciences and Medicine, Stanford University School of Medicine)

  • H. Christina Fan

    (BD Genomics)

  • Kimberly R. Cordes Metzler

    (BD Genomics)

  • Georgia Panagiotakos

    (The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California)

  • Nicholas Thom

    (Center for Sleep Sciences and Medicine, Stanford University School of Medicine)

  • Nancy A. O’Rourke

    (Center for Sleep Sciences and Medicine, Stanford University School of Medicine)

  • Lars M. Steinmetz

    (Stanford University School of Medicine
    Stanford Genome Technology Center, Stanford University
    European Molecular Biology Laboratory (EMBL), Genome Biology Unit)

  • Jonathan A. Bernstein

    (Stanford University School of Medicine)

  • Joachim Hallmayer

    (Center for Sleep Sciences and Medicine, Stanford University School of Medicine)

  • John R. Huguenard

    (Stanford University School of Medicine)

  • Sergiu P. Paşca

    (Center for Sleep Sciences and Medicine, Stanford University School of Medicine)

Abstract

The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome—a neurodevelopmental disorder that is caused by mutations in the CaV1.2 calcium channel—interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.

Suggested Citation

  • Fikri Birey & Jimena Andersen & Christopher D. Makinson & Saiful Islam & Wu Wei & Nina Huber & H. Christina Fan & Kimberly R. Cordes Metzler & Georgia Panagiotakos & Nicholas Thom & Nancy A. O’Rourke , 2017. "Assembly of functionally integrated human forebrain spheroids," Nature, Nature, vol. 545(7652), pages 54-59, May.
    • Handle: RePEc:nat:nature:v:545:y:2017:i:7652:d:10.1038_nature22330
    DOI: 10.1038/nature22330
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    Cited by:

    1. Elaine T. Lim & Yingleong Chan & Pepper Dawes & Xiaoge Guo & Serkan Erdin & Derek J. C. Tai & Songlei Liu & Julia M. Reichert & Mannix J. Burns & Ying Kai Chan & Jessica J. Chiang & Katharina Meyer & , 2022. "Orgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Yanmei Zhang & Qifan Hu & Yuquan Pei & Hao Luo & Zixuan Wang & Xinxin Xu & Qing Zhang & Jianli Dai & Qianqian Wang & Zilian Fan & Yongcong Fang & Min Ye & Binhan Li & Mailin Chen & Qi Xue & Qingfeng Z, 2024. "A patient-specific lung cancer assembloid model with heterogeneous tumor microenvironments," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Yueqi Wang & Simone Chiola & Guang Yang & Chad Russell & Celeste J. Armstrong & Yuanyuan Wu & Jay Spampanato & Paisley Tarboton & H. M. Arif Ullah & Nicolas U. Edgar & Amelia N. Chang & David A. Harmi, 2022. "Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes," Nature Communications, Nature, vol. 13(1), pages 1-25, December.
    4. Maisumu Gulimiheranmu & Shuang Li & Junmei Zhou, 2021. "In Vitro Recapitulation of Neuropsychiatric Disorders with Pluripotent Stem Cells-Derived Brain Organoids," IJERPH, MDPI, vol. 18(23), pages 1-14, November.
    5. Tatsuya Osaki & Tomoya Duenki & Siu Yu A. Chow & Yasuhiro Ikegami & Romain Beaubois & Timothée Levi & Nao Nakagawa-Tamagawa & Yoji Hirano & Yoshiho Ikeuchi, 2024. "Complex activity and short-term plasticity of human cerebral organoids reciprocally connected with axons," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Tal Sharf & Tjitse Molen & Stella M. K. Glasauer & Elmer Guzman & Alessio P. Buccino & Gabriel Luna & Zhuowei Cheng & Morgane Audouard & Kamalini G. Ranasinghe & Kiwamu Kudo & Srikantan S. Nagarajan &, 2022. "Functional neuronal circuitry and oscillatory dynamics in human brain organoids," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    7. Julien G. Roth & Lucia G. Brunel & Michelle S. Huang & Yueming Liu & Betty Cai & Sauradeep Sinha & Fan Yang & Sergiu P. Pașca & Sungchul Shin & Sarah C. Heilshorn, 2023. "Spatially controlled construction of assembloids using bioprinting," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Lauren Rylaarsdam & Jennifer Rakotomamonjy & Eleanor Pope & Alicia Guemez-Gamboa, 2024. "iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    9. Fabio Papes & Antonio P. Camargo & Janaina S. Souza & Vinicius M. A. Carvalho & Ryan A. Szeto & Erin LaMontagne & José R. Teixeira & Simoni H. Avansini & Sandra M. Sánchez-Sánchez & Thiago S. Nakahara, 2022. "Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content," Nature Communications, Nature, vol. 13(1), pages 1-26, December.
    10. Anna Pagliaro & Roxy Finger & Iris Zoutendijk & Saskia Bunschuh & Hans Clevers & Delilah Hendriks & Benedetta Artegiani, 2023. "Temporal morphogen gradient-driven neural induction shapes single expanded neuroepithelium brain organoids with enhanced cortical identity," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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