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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

Citation

Hernandez, D and Rooney, LA and Daniszewski, M and Gulluyan, L and Liang, HH and Cook, AL and Hewitt, AL and Pebay, A, 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 ISSN 2629-3277 (2021) [Refereed Article]

Copyright Statement

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

DOI: doi:10.1007/s12015-021-10147-5

Abstract

Apolipoprotein E (APOE) is the most important susceptibility gene for late onset of Alzheimer’s disease (AD), with the presence of APOE-ε4 associated with increased risk of developing AD. Here, we reprogrammed human fibroblasts from individuals with different APOE-ε genotypes into induced pluripotent stem cells (iPSCs), and generated isogenic lines with different APOE profiles. Following characterisation of the newly established iPSC lines, we used an unguided/unpatterning differentiation method to generate six-month-old cerebral organoids from all iPSC lines to assess the suitability of this in vitro system to measure APOE, β amyloid, and Tau phosphorylation levels. We identified variabilities in the organoids’ cell composition between 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 one site of Tau phosphorylation which was higher in the APOE-ε4/ε4 organoids. These data describe that pathological hallmarks of AD are observed in cerebral organoids, and that their variation is mainly independent of the APOE-ε status of the cells, but associated 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 Details

Item Type:Refereed Article
Keywords:cerebral organoid, human induced pluripotent stem cell, APOE, tau, β amyloid, CRISPR/Cas9
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biomedical and clinical sciences
UTAS Author:Cook, AL (Associate Professor Tony Cook)
UTAS Author:Hewitt, AL (Professor Alex Hewitt)
ID Code:145020
Year Published:2021
Web of Science® Times Cited:2
Deposited By:Wicking Dementia Research and Education Centre
Deposited On:2021-06-24
Last Modified:2021-09-21
Downloads:0

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