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Culture variabilities of human iPSC-derived cerebral organoids are a major Issue for the modelling of phenotypes observed in Alzheimer's Disease

Hernandez, D, Rooney, LA, Daniszewski, M, Gulluyan, L, Liang, HH, Cook, AL ORCID: 0000-0003-1770-7910, Hewitt, AL ORCID: 0000-0002-5123-5999 and Pebay, A 2021 , 'Culture variabilities of human iPSC-derived cerebral organoids are a major Issue for the modelling of phenotypes observed in Alzheimer's Disease' , Stem Cell Reviews and Reports , doi: 10.1007/s12015-021-10147-5.

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Apolipoprotein E (APOE) is the most important susceptibility gene for late onset of Alzheimer’s disease (AD), with the presenceof APOE-ε4 associated with increased risk of developing AD. Here, we reprogrammed human fibroblasts from individuals withdifferent APOE-ε genotypes into induced pluripotent stem cells (iPSCs), and generated isogenic lines with different APOEprofiles. Following characterisation of the newly established iPSC lines, we used an unguided/unpatterning differentiationmethod to generate six-month-old cerebral organoids from all iPSC lines to assess the suitability of this in vitro system tomeasure APOE, β amyloid, and Tau phosphorylation levels. We identified variabilities in the organoids’ cell compositionbetween cell lines, and between batches of differentiation for each cell line. We observed more homogenous cerebral organoids,and similar levels of APOE, β amyloid, and Tau when using the CRISPR-edited APOE isogenic lines, with the exception of onesite of Tau phosphorylation which was higher in the APOE-ε4/ε4 organoids. These data describe that pathological hallmarks ofAD are observed in cerebral organoids, and that their variation is mainly independent of the APOE-ε status of the cells, butassociated with the high variability of cerebral organoid differentiation. It demonstrates that the cell-line-to-cell-line and batch-to batch variabilities need to be considered when using cerebral organoids.

Item Type: Article
Authors/Creators:Hernandez, D and Rooney, LA and Daniszewski, M and Gulluyan, L and Liang, HH and Cook, AL and Hewitt, AL and Pebay, A
Keywords: cerebral organoid, human induced pluripotent stem cell, APOE, tau, β amyloid, CRISPR/Cas9
Journal or Publication Title: Stem Cell Reviews and Reports
Publisher: Humana Press
ISSN: 2629-3277
DOI / ID Number: 10.1007/s12015-021-10147-5
Copyright Information:

Copyright The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

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