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Large-scale organoid study suggests effects of trisomy 21 on early fetal neurodevelopment are more subtle than variability between isogenic lines and experiments

Czerminski, Jan T
King, Oliver D
Lawrence, Jeanne B
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Abstract

This study examines cortical organoids generated from a panel of isogenic trisomic and disomic iPSC lines (subclones) as a model of early fetal brain development in Down syndrome (DS). An initial experiment comparing organoids from one trisomic and one disomic line showed many genome-wide transcriptomic differences and modest differences in cell-type proportions, suggesting there may be a neurodevelopmental phenotype that is due to trisomy of chr21. To better control for multiple sources of variation, we undertook a highly robust study of ∼1,200 organoids using an expanded panel of six all-isogenic lines, three disomic, and three trisomic. The power of this experimental design was indicated by strong detection of the ∼1.5-fold difference in chr21 genes. However, the numerous expression differences in non-chr21 genes seen in the smaller experiment fell away, and the differences in cell-type representation between lines did not correlate with trisomy 21. Results suggest that the initial smaller experiment picked up differences between small organoid samples and individual isogenic lines, which "averaged out" in the larger panel of isogenic lines. Our results indicate that even when organoid and batch variability are better controlled for, variation between isogenic cell lines (even subclones) may obscure, or be conflated with, subtle neurodevelopmental phenotypes that may be present in ∼2nd trimester DS brain development. Interestingly, despite this variability between organoid batches and lines, and the "fetal stage" of these organoids, an increase in secreted Aβ40 peptide levels-an Alzheimer-related cellular phenotype-was more strongly associated with trisomy 21 status than were neurodevelopmental shifts in cell-type composition.

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Czerminski JT, King OD, Lawrence JB. Large-scale organoid study suggests effects of trisomy 21 on early fetal neurodevelopment are more subtle than variability between isogenic lines and experiments. Front Neurosci. 2023 Feb 3;16:972201. doi: 10.3389/fnins.2022.972201. PMID: 36817096; PMCID: PMC9935940.

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DOI
10.3389/fnins.2022.972201
PubMed ID
36817096
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Funding and Acknowledgements
We appreciate the support of NIH–R01HD091357, and R01HD094788 to JL; F30HD086975 and T32GM107000 to JC.
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Much of this work was originally part of a dissertation by JC (Czerminski, 2019) (http://hdl.handle.net/20.500.14038/31257), and a version with some revisions and extensions has been posted as a preprint to bioRxiv (Czerminski et al., 2022). Many of the analyses have been updated and expanded in the present manuscript, in part in response to helpful suggestions by the reviewers.

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© 2023 Czerminski, King and Lawrence. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.; Attribution 4.0 International