Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening
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 d...
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55226-6 |
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| author | Anand Ramani Giovanni Pasquini Niklas J. Gerkau Vaibhav Jadhav Omkar Suhas Vinchure Nazlican Altinisik Hannes Windoffer Sarah Muller Ina Rothenaigner Sean Lin Aruljothi Mariappan Dhanasekaran Rathinam Ali Mirsaidi Olivier Goureau Lucia Ricci-Vitiani Quintino Giorgio D’Alessandris Bernd Wollnik Alysson Muotri Limor Freifeld Nathalie Jurisch-Yaksi Roberto Pallini Christine R. Rose Volker Busskamp Elke Gabriel Kamyar Hadian Jay Gopalakrishnan |
| author_facet | Anand Ramani Giovanni Pasquini Niklas J. Gerkau Vaibhav Jadhav Omkar Suhas Vinchure Nazlican Altinisik Hannes Windoffer Sarah Muller Ina Rothenaigner Sean Lin Aruljothi Mariappan Dhanasekaran Rathinam Ali Mirsaidi Olivier Goureau Lucia Ricci-Vitiani Quintino Giorgio D’Alessandris Bernd Wollnik Alysson Muotri Limor Freifeld Nathalie Jurisch-Yaksi Roberto Pallini Christine R. Rose Volker Busskamp Elke Gabriel Kamyar Hadian Jay Gopalakrishnan |
| author_sort | Anand Ramani |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d5025635706e4d8fadd634ef9f4403da |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d5025635706e4d8fadd634ef9f4403da2025-02-09T12:43:47ZengNature PortfolioNature Communications2041-17232024-12-0115112010.1038/s41467-024-55226-6Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screeningAnand Ramani0Giovanni Pasquini1Niklas J. Gerkau2Vaibhav Jadhav3Omkar Suhas Vinchure4Nazlican Altinisik5Hannes Windoffer6Sarah Muller7Ina Rothenaigner8Sean Lin9Aruljothi Mariappan10Dhanasekaran Rathinam11Ali Mirsaidi12Olivier Goureau13Lucia Ricci-Vitiani14Quintino Giorgio D’Alessandris15Bernd Wollnik16Alysson Muotri17Limor Freifeld18Nathalie Jurisch-Yaksi19Roberto Pallini20Christine R. Rose21Volker Busskamp22Elke Gabriel23Kamyar Hadian24Jay Gopalakrishnan25Institute of Human Genetics, University Hospital, Friedrich-Schiller-Universität JenaDepartment of Ophthalmology, University Hospital Bonn, Medical FacultyInstitute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich-Heine-UniversitätInstitute of Human Genetics, University Hospital, Friedrich-Schiller-Universität JenaInstitute of Human Genetics, University Hospital, Friedrich-Schiller-Universität JenaInstitute of Human Genetics, University Hospital, Friedrich-Schiller-Universität JenaInstitute of Human Genetics, University Hospital, Friedrich-Schiller-Universität JenaInstitute of Human Genetics, University Hospital, Friedrich-Schiller-Universität JenaResearch Unit Signaling and Translation, Helmholtz Zentrum MünchenResearch Unit Signaling and Translation, Helmholtz Zentrum MünchenInstitute of Human Genetics, University Hospital, Friedrich-Schiller-Universität JenaInstitute of Human Genetics, University Hospital, Friedrich-Schiller-Universität JenaKugelmeiers LtdInstitut de la Vision, Sorbonne Université, INSERM, CNRSDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299Department of Neuroscience, Neurosurgery Section, Università Cattolica del Sacro CuoreInstitute of Human Genetics, University Medical Center GöttingenUniversity of California San Diego, School of Medicine, Department of Pediatrics/Rady Children’s Hospital-San DiegoDepartment of Biomedical Engineering, Technion-Israel Institute of TechnologyDepartment of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and TechnologyDepartment of Neuroscience, Neurosurgery Section, Università Cattolica del Sacro CuoreInstitute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich-Heine-UniversitätDepartment of Ophthalmology, University Hospital Bonn, Medical FacultyInstitute of Human Genetics, University Hospital, Heinrich-Heine-UniversitätResearch Unit Signaling and Translation, Helmholtz Zentrum MünchenInstitute of Human Genetics, University Hospital, Friedrich-Schiller-Universität JenaAbstract 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.https://doi.org/10.1038/s41467-024-55226-6 |
| spellingShingle | Anand Ramani Giovanni Pasquini Niklas J. Gerkau Vaibhav Jadhav Omkar Suhas Vinchure Nazlican Altinisik Hannes Windoffer Sarah Muller Ina Rothenaigner Sean Lin Aruljothi Mariappan Dhanasekaran Rathinam Ali Mirsaidi Olivier Goureau Lucia Ricci-Vitiani Quintino Giorgio D’Alessandris Bernd Wollnik Alysson Muotri Limor Freifeld Nathalie Jurisch-Yaksi Roberto Pallini Christine R. Rose Volker Busskamp Elke Gabriel Kamyar Hadian Jay Gopalakrishnan Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening Nature Communications |
| title | Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening |
| title_full | Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening |
| title_fullStr | Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening |
| title_full_unstemmed | Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening |
| title_short | Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening |
| title_sort | reliability of high quantity human brain organoids for modeling microcephaly glioma invasion and drug screening |
| url | https://doi.org/10.1038/s41467-024-55226-6 |
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