Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening
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.
Authors
- Volker Busskamp (ORCID: https://orcid.org/0000-0001-7517-8944)
- Omkar Suhas Vinchure (ORCID: https://orcid.org/0000-0003-0809-4235)
- Sean Lin (ORCID: https://orcid.org/0000-0001-9691-5149)
- Christine R. Rose (ORCID: https://orcid.org/0000-0002-9684-3592)
- Nathalie Jurisch‐Yaksi (ORCID: https://orcid.org/0000-0002-8767-6120)
- Lucia Ricci‐Vitiani (ORCID: https://orcid.org/0000-0001-7336-5615)
- Anand Ramani (ORCID: https://orcid.org/0000-0002-2380-8649)
- Kamyar Hadian (ORCID: https://orcid.org/0000-0001-8727-2575)
- Giovanni Pasquini (ORCID: https://orcid.org/0000-0002-5750-6307)
- Nazlican Altinisik
- Ina Rothenaigner
- Dhanasekaran Rathinam (ORCID: https://orcid.org/0009-0000-3117-7181)
- Niklas J. Gerkau (ORCID: https://orcid.org/0000-0002-7721-3966)
- Olivier Goureau (ORCID: https://orcid.org/0000-0001-7730-9143)
- Roberto Pallini (ORCID: https://orcid.org/0000-0002-4611-8827)
- Vaibhav Jadhav (ORCID: https://orcid.org/0000-0002-1873-1894)
- Elke Gabriel (ORCID: https://orcid.org/0000-0001-7473-0530)
- Bernd Wollnik (ORCID: https://orcid.org/0000-0003-2589-0364)
- Quintino Giorgio D’Alessandris (ORCID: https://orcid.org/0000-0002-2953-9291)
- Limor Freifeld (ORCID: https://orcid.org/0000-0002-0739-6947)
- Ali Mirsaidi
- Sarah M. Muller
- Jay Gopalakrishnan (ORCID: https://orcid.org/0000-0001-5907-3982)
- Aruljothi Mariappan (ORCID: https://orcid.org/0000-0001-5286-9806)
- Alysson R. Muotri
- Hannes Windoffer
Institutions
- Università Cattolica del Sacro Cuore (IT)
- Centre National de la Recherche Scientifique (FR)
- Institut de la Vision (FR)
- Inserm (FR)
- Technion – Israel Institute of Technology (IL)
- Norwegian University of Science and Technology (NO)
- Istituto Superiore di Sanità (IT)
- University Hospital Bonn (DE)
- Helmholtz Zentrum München (DE)
- University of California San Diego (US)
- Sorbonne Université (FR)
- Rady Children's Hospital-San Diego (US)
- Düsseldorf University Hospital (DE)
- Universitätsmedizin Göttingen (DE)
- Jena University Hospital (DE)
- Cellular Research (United States) (US)
- Heinrich Heine University Düsseldorf (DE)
- Friedrich Schiller University Jena (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-19
- DOI
- https://doi.org/10.1038/s41467-024-55226-6
- Citations
- 23
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 5.38
Funders
- Deutsche Forschungsgemeinschaft
- Volkswagen Foundation
- Bundesministerium für Bildung und Forschung
- Fritz Thyssen Stiftung
- Associazione Italiana per la Ricerca sul Cancro
- Norges Forskningsråd
- Deutsche Krebshilfe
- Rheinische Friedrich-Wilhelms-Universität Bonn