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Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening

Author

Listed:
  • Anand Ramani

    (Friedrich-Schiller-Universität Jena)

  • Giovanni Pasquini

    (Medical Faculty)

  • Niklas J. Gerkau

    (Heinrich-Heine-Universität)

  • Vaibhav Jadhav

    (Friedrich-Schiller-Universität Jena)

  • Omkar Suhas Vinchure

    (Friedrich-Schiller-Universität Jena)

  • Nazlican Altinisik

    (Friedrich-Schiller-Universität Jena)

  • Hannes Windoffer

    (Friedrich-Schiller-Universität Jena)

  • Sarah Muller

    (Friedrich-Schiller-Universität Jena)

  • Ina Rothenaigner

    (Helmholtz Zentrum München)

  • Sean Lin

    (Helmholtz Zentrum München)

  • Aruljothi Mariappan

    (Friedrich-Schiller-Universität Jena)

  • Dhanasekaran Rathinam

    (Friedrich-Schiller-Universität Jena)

  • Ali Mirsaidi

    (Kugelmeiers Ltd)

  • Olivier Goureau

    (CNRS)

  • Lucia Ricci-Vitiani

    (Viale Regina Elena 299)

  • Quintino Giorgio D’Alessandris

    (Università Cattolica del Sacro Cuore)

  • Bernd Wollnik

    (University Medical Center Göttingen)

  • Alysson Muotri

    (Department of Pediatrics/Rady Children’s Hospital-San Diego
    Stem Cell Program)

  • Limor Freifeld

    (Technion-Israel Institute of Technology)

  • Nathalie Jurisch-Yaksi

    (Norwegian University of Science and Technology)

  • Roberto Pallini

    (Università Cattolica del Sacro Cuore)

  • Christine R. Rose

    (Heinrich-Heine-Universität)

  • Volker Busskamp

    (Medical Faculty)

  • Elke Gabriel

    (Heinrich-Heine-Universität)

  • Kamyar Hadian

    (Helmholtz Zentrum München)

  • Jay Gopalakrishnan

    (Friedrich-Schiller-Universität Jena)

Abstract

Brain organoids offer unprecedented insights into brain development and disease modeling and hold promise for drug screening. Significant hindrances, however, are morphological and cellular heterogeneity, inter-organoid size differences, cellular stress, and poor reproducibility. Here, we describe a method that reproducibly generates thousands of organoids across multiple hiPSC lines. These High Quantity brain organoids (Hi-Q brain organoids) exhibit reproducible cytoarchitecture, cell diversity, and functionality, are free from ectopically active cellular stress pathways, and allow cryopreservation and re-culturing. Patient-derived Hi-Q brain organoids recapitulate distinct forms of developmental defects: primary microcephaly due to a mutation in CDK5RAP2 and progeria-associated defects of Cockayne syndrome. Hi-Q brain organoids displayed a reproducible invasion pattern for a given patient-derived glioma cell line. This enabled a medium-throughput drug screen to identify Selumetinib and Fulvestrant, as inhibitors of glioma invasion in vivo. Thus, the Hi-Q approach can easily be adapted to reliably harness brain organoids’ application for personalized neurogenetic disease modeling and drug discovery.

Suggested Citation

  • Anand Ramani & Giovanni Pasquini & Niklas J. Gerkau & Vaibhav Jadhav & Omkar Suhas Vinchure & Nazlican Altinisik & Hannes Windoffer & Sarah Muller & Ina Rothenaigner & Sean Lin & Aruljothi Mariappan &, 2024. "Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-55226-6
    DOI: 10.1038/s41467-024-55226-6
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