Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions

Pereira, João D.; Dubreuil, Daniel; Devlin, Anna-Claire; Held, Aaron; Sapir, Yechiam; Berezovski, Eugene; Hawrot, James; Dorfman, Katherine; Chander, Vignesh; Wainger, Brian J.

doi:10.1038/s41467-021-24776-4

Cited by 91 publications

(104 citation statements)

References 110 publications

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“…Even if iPS-derived macrophages/microglia were the first generated immune cells, there is no report yet about iPSC modeling of ALS or FTD macrophage/microglia co-cultures with neurons. In their recent study, Pereira et al (2021) describes the generation of human sensorimotor organoids with iPSC from ALS patients. They showed that these organoids contain microglia-like cells, but their study was not focused on the phenotypes of these cells, but rather on defects at the level of NMJs ( Pereira et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…In their recent study, Pereira et al (2021) describes the generation of human sensorimotor organoids with iPSC from ALS patients. They showed that these organoids contain microglia-like cells, but their study was not focused on the phenotypes of these cells, but rather on defects at the level of NMJs ( Pereira et al, 2021 ). Another study describes the generation of cerebral organoids from iPSC of 3 FTD patients mutated in the tau gene ( Bowles et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Most of current studies focused on microglia addition to organoids and modeling of Alzheimer’s or Parkinson‘s defects, making the proof that the different iPSC based models could bring new knowledge for ALS and FTD. Recently, the generation of microglia-like cells in human sensorimotor organoids derived from ALS iPSC was reported ( Pereira et al, 2021 ), proving that these cells can arise and be phenotypically studied in these models.…”

Section: Ipsc To Model Immune Reactivity In Amyotrophic Lateral Sclerosis and Frontotemporal Dementiamentioning

confidence: 99%

See 2 more Smart Citations

Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

Liu

Karpf

Bohl

2021

Front. Mol. Neurosci.

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Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ipsc To Model Immune Reactivity In Amyotrophic Lateral Sclerosis and Frontotemporal Dementiamentioning

confidence: 99%

See 1 more Smart Citation

Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

Liu

Karpf

Bohl

2021

Front. Mol. Neurosci.

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“…Furthermore, organoid culture systems allow for the differentiation of multiple cell types to form a miniature version and experimentally approachable model of the tissue of interest ( Vieira de Sa et al, 2021 ). Recently, iPSC-derived human sensorimotor organoids, which contain motor and sensory neurons, skeletal muscle, astrocytes, microglia, and vasculature, have been used to assess how familial ALS mutations affect NMJ and muscle function in vitro ( Pereira et al, 2021 ).…”

Section: Enhancing Cell Maturity and Exploring Cell Biological Mechanismsmentioning

confidence: 99%

An Integrated Approach to Studying Rare Neuromuscular Diseases Using Animal and Human Cell-Based Models

Hines

Lutz

Murray

et al. 2022

Front. Cell Dev. Biol.

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As sequencing technology improves, the identification of new disease-associated genes and new alleles of known genes is rapidly increasing our understanding of the genetic underpinnings of rare diseases, including neuromuscular diseases. However, precisely because these disorders are rare and often heterogeneous, they are difficult to study in patient populations. In parallel, our ability to engineer the genomes of model organisms, such as mice or rats, has gotten increasingly efficient through techniques such as CRISPR/Cas9 genome editing, allowing the creation of precision human disease models. Such in vivo model systems provide an efficient means for exploring disease mechanisms and identifying therapeutic strategies. Furthermore, animal models provide a platform for preclinical studies to test the efficacy of those strategies. Determining whether the same mechanisms are involved in the human disease and confirming relevant parameters for treatment ideally involves a human experimental system. One system currently being used is induced pluripotent stem cells (iPSCs), which can then be differentiated into the relevant cell type(s) for in vitro confirmation of disease mechanisms and variables such as target engagement. Here we provide a demonstration of these approaches using the example of tRNA-synthetase-associated inherited peripheral neuropathies, rare forms of Charcot-Marie-Tooth disease (CMT). Mouse models have led to a better understanding of both the genetic and cellular mechanisms underlying the disease. To determine if the mechanisms are similar in human cells, we will use genetically engineered iPSC-based models. This will allow comparisons of different CMT-associated GARS alleles in the same genetic background, reducing the variability found between patient samples and simplifying the availability of cell-based models for a rare disease. The necessity of integrating mouse and human models, strategies for accomplishing this integration, and the challenges of doing it at scale are discussed using recently published work detailing the cellular mechanisms underlying GARS-associated CMT as a framework.

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“…Moreover, fusion of brain organoids is currently used to model interactions between different brain regions [71]. The development of additional tissues, like bilateral optical vesicles [72], or even the fusion with muscle cells for the development of motoneurons and of neuromuscular junctions, [73], [74] have been performed and these studies exemplified the advantages ahead using organoids to study human brain diseases. Thus, these approaches will prove useful in the future to investigate in further detail, how FOXG1 influences later neural development, its potential influence on tissue interaction, on entire organ function, and even multi-organ interplay.…”

Section: Future Of Foxg1 Syndrome Modelling Therapeutic Prospects and Limitationsmentioning

confidence: 99%

Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

Akol¹,

Gather²,

Vogel³

2021

Preprint

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Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signalling pathways and transcription programs. Forkhead Box G1 (FOXG1) is one of the master regulators that plays fundamental roles in forebrain development, from the timing of neurogenesis to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as increased yield of information from high throughput omics opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems to highlight prospects of research and possible clinical interventions.

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Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions

Cited by 91 publications

References 110 publications

Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

An Integrated Approach to Studying Rare Neuromuscular Diseases Using Animal and Human Cell-Based Models

Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

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