1. Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening.
- Author
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Ramani, Anand, Pasquini, Giovanni, Gerkau, Niklas, Jadhav, Vaibhav, Vinchure, Omkar, Altinisik, Nazlican, Windoffer, Hannes, Muller, Sarah, Rothenaigner, Ina, Lin, Sean, Mariappan, Aruljothi, Rathinam, Dhanasekaran, Mirsaidi, Ali, Goureau, Olivier, Ricci-Vitiani, Lucia, DAlessandris, Quintino, Wollnik, Bernd, Muotri, Alysson, Freifeld, Limor, Jurisch-Yaksi, Nathalie, Pallini, Roberto, Rose, Christine, Busskamp, Volker, Gabriel, Elke, Hadian, Kamyar, and Gopalakrishnan, Jay
- Subjects
Organoids ,Humans ,Microcephaly ,Glioma ,Drug Evaluation ,Preclinical ,Brain ,Brain Neoplasms ,Animals ,Reproducibility of Results ,Benzimidazoles ,Mice ,Cell Line ,Tumor ,Neoplasm Invasiveness - 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.
- Published
- 2024