Human Induced Pluripotent Stem Cell-Derived TDP-43 Mutant Neurons Exhibit Consistent Functional Phenotypes Across Multiple Gene Edited Lines Despite Transcriptomic and Splicing Discrepancies
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...
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Frontiers Media S.A.
2021-09-01
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Series: | Frontiers in Cell and Developmental Biology |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.728707/full |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alec S. T. Smith Alec S. T. Smith Changho Chun Jennifer Hesson Jennifer Hesson Julie Mathieu Julie Mathieu Paul N. Valdmanis David L. Mack David L. Mack David L. Mack David L. Mack Byung-Ok Choi Byung-Ok Choi Byung-Ok Choi Deok-Ho Kim Deok-Ho Kim Deok-Ho Kim Deok-Ho Kim Mark Bothwell Mark Bothwell |
spellingShingle |
Alec S. T. Smith Alec S. T. Smith Changho Chun Jennifer Hesson Jennifer Hesson Julie Mathieu Julie Mathieu Paul N. Valdmanis David L. Mack David L. Mack David L. Mack David L. Mack Byung-Ok Choi Byung-Ok Choi Byung-Ok Choi Deok-Ho Kim Deok-Ho Kim Deok-Ho Kim Deok-Ho Kim Mark Bothwell Mark Bothwell Human Induced Pluripotent Stem Cell-Derived TDP-43 Mutant Neurons Exhibit Consistent Functional Phenotypes Across Multiple Gene Edited Lines Despite Transcriptomic and Splicing Discrepancies Frontiers in Cell and Developmental Biology ALS (amyotrophic lateral sclerosis) iPSC (induced pluripotent stem cell) transcriptomics electrophysiologic analysis disease model |
author_facet |
Alec S. T. Smith Alec S. T. Smith Changho Chun Jennifer Hesson Jennifer Hesson Julie Mathieu Julie Mathieu Paul N. Valdmanis David L. Mack David L. Mack David L. Mack David L. Mack Byung-Ok Choi Byung-Ok Choi Byung-Ok Choi Deok-Ho Kim Deok-Ho Kim Deok-Ho Kim Deok-Ho Kim Mark Bothwell Mark Bothwell |
author_sort |
Alec S. T. Smith |
title |
Human Induced Pluripotent Stem Cell-Derived TDP-43 Mutant Neurons Exhibit Consistent Functional Phenotypes Across Multiple Gene Edited Lines Despite Transcriptomic and Splicing Discrepancies |
title_short |
Human Induced Pluripotent Stem Cell-Derived TDP-43 Mutant Neurons Exhibit Consistent Functional Phenotypes Across Multiple Gene Edited Lines Despite Transcriptomic and Splicing Discrepancies |
title_full |
Human Induced Pluripotent Stem Cell-Derived TDP-43 Mutant Neurons Exhibit Consistent Functional Phenotypes Across Multiple Gene Edited Lines Despite Transcriptomic and Splicing Discrepancies |
title_fullStr |
Human Induced Pluripotent Stem Cell-Derived TDP-43 Mutant Neurons Exhibit Consistent Functional Phenotypes Across Multiple Gene Edited Lines Despite Transcriptomic and Splicing Discrepancies |
title_full_unstemmed |
Human Induced Pluripotent Stem Cell-Derived TDP-43 Mutant Neurons Exhibit Consistent Functional Phenotypes Across Multiple Gene Edited Lines Despite Transcriptomic and Splicing Discrepancies |
title_sort |
human induced pluripotent stem cell-derived tdp-43 mutant neurons exhibit consistent functional phenotypes across multiple gene edited lines despite transcriptomic and splicing discrepancies |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2021-09-01 |
description |
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-43M337V and TDP-43Q331K were compared with in-house derived lines engineered to express the TDP-43Q331K 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. |
topic |
ALS (amyotrophic lateral sclerosis) iPSC (induced pluripotent stem cell) transcriptomics electrophysiologic analysis disease model |
url |
https://www.frontiersin.org/articles/10.3389/fcell.2021.728707/full |
work_keys_str_mv |
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doaj-b867e9f17fc7469794bf34151937519a2021-09-29T05:31:45ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-09-01910.3389/fcell.2021.728707728707Human Induced Pluripotent Stem Cell-Derived TDP-43 Mutant Neurons Exhibit Consistent Functional Phenotypes Across Multiple Gene Edited Lines Despite Transcriptomic and Splicing DiscrepanciesAlec S. T. Smith0Alec S. T. Smith1Changho Chun2Jennifer Hesson3Jennifer Hesson4Julie Mathieu5Julie Mathieu6Paul N. Valdmanis7David L. Mack8David L. Mack9David L. Mack10David L. Mack11Byung-Ok Choi12Byung-Ok Choi13Byung-Ok Choi14Deok-Ho Kim15Deok-Ho Kim16Deok-Ho Kim17Deok-Ho Kim18Mark Bothwell19Mark Bothwell20Department of Physiology and Biophysics, University of Washington, Seattle, WA, United StatesInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United StatesDepartment of Bioengineering, University of Washington, Seattle, WA, United StatesInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United StatesDepartment of Comparative Medicine, University of Washington, Seattle, WA, United StatesInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United StatesDepartment of Comparative Medicine, University of Washington, Seattle, WA, United StatesDivision of Medical Genetics, University of Washington, Seattle, WA, United StatesDepartment of Physiology and Biophysics, University of Washington, Seattle, WA, United StatesInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United StatesDepartment of Bioengineering, University of Washington, Seattle, WA, United StatesDepartment of Rehabilitation Medicine, University of Washington, Seattle, WA, United StatesDepartment of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South KoreaStem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, South KoreaDepartment of Health Sciences and Technology, The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, South KoreaDepartment of Bioengineering, University of Washington, Seattle, WA, United States0Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States1Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Physiology and Biophysics, University of Washington, Seattle, WA, United StatesInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United StatesGene 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-43M337V and TDP-43Q331K were compared with in-house derived lines engineered to express the TDP-43Q331K 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.728707/fullALS (amyotrophic lateral sclerosis)iPSC (induced pluripotent stem cell)transcriptomicselectrophysiologic analysisdisease model |