PuSH - Publikationsserver des Helmholtz Zentrums München: Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening.

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Ramani, A.* ; Pasquini, G.* ; Gerkau, N.J.* ; Jadhav, V.* ; Vinchure, O.S.* ; Altinisik, N.* ; Windoffer, H.* ; Müller, S.* ; Rothenaigner, I. ; Lin, S. ; Mariappan, A.* ; Rathinam, D.* ; Mirsaidi, A.* ; Goureau, O.* ; Ricci-Vitiani, L.* ; D'Alessandris, Q.G.* ; Wollnik, B.* ; Muotri, A.* ; Freifeld, L.* ; Jurisch-Yaksi, N.* ; Pallini, R.* ; Rose, C.R.* ; Busskamp, V.* ; Gabriel, E.* ; Hadian, K. ; Gopalakrishnan, J.*

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

Nat. Commun. 15:10703 (2024)

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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.

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