期刊
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2021.728707
关键词
ALS (amyotrophic lateral sclerosis); iPSC (induced pluripotent stem cell); transcriptomics; electrophysiologic analysis; disease model
资金
- NICHD NIH HHS [P50 HD103524] Funding Source: Medline
- NIDDK NIH HHS [P30 DK017047] Funding Source: Medline
Gene editing technologies can enhance modeling of inheritable neurodegenerative diseases, but careful comparison of multiple cell lines is needed to ensure consistency and accuracy.
Gene editing technologies hold great potential to enhance our ability to model inheritable neurodegenerative diseases. Specifically, engineering multiple amyotrophic lateral sclerosis (ALS) mutations into isogenic cell populations facilitates determination of whether different causal mutations cause pathology via shared mechanisms, and provides the capacity to separate these mechanisms from genotype-specific effects. As gene-edited, cell-based models of human disease become more commonplace, there is an urgent need to verify that these models constitute consistent and accurate representations of native biology. Here, commercially sourced, induced pluripotent stem cell-derived motor neurons from Cellular Dynamics International, edited to express the ALS-relevant mutations TDP-43(M337V) and TDP-43(Q331K) were compared with in-house derived lines engineered to express the TDP-43(Q331K) mutation within the WTC11 background. Our results highlight electrophysiological and mitochondrial deficits in these edited cells that correlate with patient-derived cells, suggesting a consistent cellular phenotype arising from TDP-43 mutation. However, significant differences in the transcriptomic profiles and splicing behavior of the edited cells underscores the need for careful comparison of multiple lines when attempting to use these cells as a means to better understand the onset and progression of ALS in humans.
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