Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects

Using induced pluripotent stem cells (iPSCs) to understand the mechanisms of neurological disease holds great promise; however, there is a lack of well-curated lines from a large array of participants. Answer ALS has generated over 1,000 iPSC lines from control and amyotrophic lateral sclerosis (ALS...

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Published in:Neuron (Cambridge, Mass.) Mass.), 2023-04, Vol.111 (8), p.1191-1204.e5
Main Authors: Workman, Michael J., Lim, Ryan G., Wu, Jie, Frank, Aaron, Ornelas, Loren, Panther, Lindsay, Galvez, Erick, Perez, Daniel, Meepe, Imara, Lei, Susan, Valencia, Viviana, Gomez, Emilda, Liu, Chunyan, Moran, Ruby, Pinedo, Louis, Tsitkov, Stanislav, Ho, Ritchie, Kaye, Julia A., Thompson, Terri, Rothstein, Jeffrey D., Finkbeiner, Steven, Fraenkel, Ernest, Sareen, Dhruv, Thompson, Leslie M., Svendsen, Clive N.
Format: Article
Language:English
Subjects:
ALS
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - metabolism
Cell Differentiation
Humans
Induced Pluripotent Stem Cells - metabolism
iPSC
motor neurons
Motor Neurons - metabolism
sex differences
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Summary:Using induced pluripotent stem cells (iPSCs) to understand the mechanisms of neurological disease holds great promise; however, there is a lack of well-curated lines from a large array of participants. Answer ALS has generated over 1,000 iPSC lines from control and amyotrophic lateral sclerosis (ALS) patients along with clinical and whole-genome sequencing data. The current report summarizes cell marker and gene expression in motor neuron cultures derived from 92 healthy control and 341 ALS participants using a 32-day differentiation protocol. This is the largest set of iPSCs to be differentiated into motor neurons, and characterization suggests that cell composition and sex are significant sources of variability that need to be carefully controlled for in future studies. These data are reported as a resource for the scientific community that will utilize Answer ALS data for disease modeling using a wider array of omics being made available for these samples. [Display omitted] •Large-scale generation and differentiation of control and ALS iPSCs to motor neurons•Patient sex and cell culture composition are significant sources of variation•Male ALS cultures have more motor neurons and enrichment of stress-related pathways•Deposition of data and cell lines into public repository with additional multi-omics In this article, 433 iPSCs from control and ALS patients were differentiated into motor neurons and profiled by immunocytochemistry and RNA-seq. Results reveal sex and cell composition to be among the strongest drivers of gene expression variation, with a higher percentage of Islet1+ cells observed in male ALS patient-derived cultures.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2023.01.010