Modeling neurodevelopment in a dish with pluripotent stem cells

Imaizumi, Kent

doi:10.1111/dgd.12699

Cited by 15 publications

(7 citation statements)

References 72 publications

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“…Human iPSC-based disease models have remarkable potential to clarify disease pathogenesis and to discover effective therapies because of the discrepancy between patients and animal models ( Okano and Yamanaka, 2014 ; Imaizumi and Okano, 2021 ). Previous studies of human iPSC-based models revealed RNA misprocessing induced by TDP-43 LOF; however, these studies largely used a knock-down strategy for recapitulating TDP-43 LOF ( Klim et al, 2019 ; Prudencio et al, 2020 ), and the effect of pathogenic mutations of TDP-43 on global RNA regulation has not been extensively investigated.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Mutation of TDP-43 Impairs RNA Processing in a Cell Type-Specific Manner: Implications for the Pathogenesis of ALS/FTLD

Imaizumi

Ideno

Sato

et al. 2022

eNeuro

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Transactivating response element DNA-binding protein of 43 kDa (TDP-43), which is encoded by the TARDBP gene, is an RNA-binding protein with fundamental RNA processing activities, and its loss-of-function (LOF) has a central role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TARDBP mutations are postulated to inactivate TDP-43 functions, leading to impaired RNA processing. However, it has not been fully examined how mutant TDP-43 affects global RNA regulation, especially in human cell models. Here, we examined global RNA processing in forebrain cortical neurons derived from human induced pluripotent stem cells (iPSCs) with a pathogenic TARDBP mutation encoding the TDP-43 K263E protein. In neurons expressing mutant TDP-43, we detected disrupted RNA regulation, including global changes in gene expression, missplicing, and aberrant polyadenylation, all of which were highly similar to those induced by TDP-43 knock-down. This mutation-induced TDP-43 LOF was not because of the cytoplasmic mislocalization of TDP-43. Intriguingly, in nonneuronal cells, including iPSCs and neural progenitor cells (NPCs), we did not observe impairments in RNA processing, thus indicating that the K263E mutation results in neuron-specific LOF of TDP-43. This study characterizes global RNA processing impairments induced by mutant TDP-43 and reveals the unprecedented cell type specificity of TDP-43 LOF in ALS/FTLD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Pathogenic Mutation of TDP-43 Impairs RNA Processing in a Cell Type-Specific Manner: Implications for the Pathogenesis of ALS/FTLD

Imaizumi

Ideno

Sato

et al. 2022

eNeuro

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“…Recent advances in the induction of neuronal differentiation from pluripotent stem cells (PSCs) have led researchers to generate region-specific neurons and brain organoids [ 4 , 5 ] and to establish culture methods that more closely mimic physiological conditions through the use of microfluidic devices and co-culture with glial cells, allowing the study of axonal function and non-cell autonomic effects [ 6 ]. In vitro neuronal differentiation methods generally induce PSCs to differentiate into neuroectoderm by inhibiting SMAD signaling, followed by patterning by controlling the concentration of morphogens and compounds that activate or inhibit intracellular signaling [ 7 , 8 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Rapid and Robust Multi-Phenotypic Assay System for ALS Using Human iPS Cells with Mutations in Causative Genes

Kondo

Ebinuma

Nishikawa

et al. 2023

IJMS

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Amyotrophic lateral sclerosis (ALS) is a major life-threatening disease caused by motor neuron degeneration. More effective treatments through drug discovery are urgently needed. Here, we established an effective high-throughput screening system using induced pluripotent stem cells (iPSCs). Using a Tet-On-dependent transcription factor expression system carried on the PiggyBac vector, motor neurons were efficiently and rapidly generated from iPSCs by a single-step induction method. Induced iPSC transcripts displayed characteristics similar to those of spinal cord neurons. iPSC-generated motor neurons carried a mutation in fused in sarcoma (FUS) and superoxide dismutase 1 (SOD1) genes and had abnormal protein accumulation corresponding to each mutation. Calcium imaging and multiple electrode array (MEA) recordings demonstrated that ALS neurons were abnormally hyperexcitable. Noticeably, protein accumulation and hyperexcitability were ameliorated by treatment with rapamycin (mTOR inhibitor) and retigabine (Kv7 channel activator), respectively. Furthermore, rapamycin suppressed ALS neuronal death and hyperexcitability, suggesting that protein aggregate clearance through the activation of autophagy effectively normalized activity and improved neuronal survival. Our culture system reproduced several ALS phenotypes, including protein accumulation, hyperexcitability, and neuronal death. This rapid and robust phenotypic screening system will likely facilitate the discovery of novel ALS therapeutics and stratified and personalized medicine for sporadic motor neuron diseases.

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“…Stem cell-derived neural cells are especially powerful models of embryonic development since differentiation protocols are typically designed to closely mimic key signaling pathways during early embryogenesis (for recent reviews see Imaizumi and Okano, 2021 ; Sabitha et al, 2021 ). Stem cell-derived neurons, whether in 2D or 3D culture, have been found to exhibit gene expression signatures that are most similar to early to mid-gestational stages (Handel et al, 2016 ; Logan et al, 2020 ).…”

Section: Complementing and Building On Animal Models With Human Stem Cell Modelsmentioning

confidence: 99%

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

Knock

Julian

2021

Front. Cell. Neurosci.

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The brain is our most complex and least understood organ. Animal models have long been the most versatile tools available to dissect brain form and function; however, the human brain is highly distinct from that of standard model organisms. In addition to existing models, access to human brain cells and tissues is essential to reach new frontiers in our understanding of the human brain and how to intervene therapeutically in the face of disease or injury. In this review, we discuss current and developing culture models of human neural tissue, outlining advantages over animal models and key challenges that remain to be overcome. Our principal focus is on advances in engineering neural cells and tissue constructs from human pluripotent stem cells (PSCs), though primary human cell and slice culture are also discussed. By highlighting studies that combine animal models and human neural cell culture techniques, we endeavor to demonstrate that clever use of these orthogonal model systems produces more reproducible, physiological, and clinically relevant data than either approach alone. We provide examples across a range of topics in neuroscience research including brain development, injury, and cancer, neurodegenerative diseases, and psychiatric conditions. Finally, as testing of PSC-derived neurons for cell replacement therapy progresses, we touch on the advancements that are needed to make this a clinical mainstay.

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Modeling neurodevelopment in a dish with pluripotent stem cells

Cited by 15 publications

References 72 publications

Pathogenic Mutation of TDP-43 Impairs RNA Processing in a Cell Type-Specific Manner: Implications for the Pathogenesis of ALS/FTLD

Pathogenic Mutation of TDP-43 Impairs RNA Processing in a Cell Type-Specific Manner: Implications for the Pathogenesis of ALS/FTLD

Rapid and Robust Multi-Phenotypic Assay System for ALS Using Human iPS Cells with Mutations in Causative Genes

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

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