Image‐based deep learning reveals the responses of human motor neurons to stress and <i>VCP</i>‐related ALS

Verzat, Colombine; Harley, Jasmine; Patani, Rickie; Luisier, Raphaëlle

doi:10.1111/nan.12770

Cited by 9 publications

(2 citation statements)

References 64 publications

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“…This may be attributed to weak signal that is diminished within the noise. Despite these limitations, previous work has demonstrated that ML classification can predict FALS origin in a small number of VCP mutant lines (Verzat et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Deep Learning Analysis on Images of iPSC-derived Motor Neurons Carrying fALS-genetics Reveals Disease-Relevant Phenotypes

Atmaramani,

Dreossi,

Ford

et al. 2024

Preprint

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Amyotrophic lateral sclerosis (ALS) is a devastating condition with very limited treatment options. It is a heterogeneous disease with complex genetics and unclear etiology, making the discovery of disease-modifying interventions very challenging. To discover novel mechanisms underlying ALS, we leverage a unique platform that combines isogenic, induced pluripotent stem cell (iPSC)-derived models of disease-causing mutations with rich phenotyping via high-content imaging and deep learning models. We introduced eight mutations that cause familial ALS (fALS) into multiple donor iPSC lines, and differentiated them into motor neurons to create multiple isogenic pairs of healthy (wild-type) and sick (mutant) motor neurons. We collected extensive high-content imaging data and used machine learning (ML) to process the images, segment the cells, and learn phenotypes. Self-supervised ML was used to create a concise embedding that captured significant, ALS-relevant biological information in these images. We demonstrate that ML models trained on core cell morphology alone can accurately predict TDP-43 mislocalization, a known phenotypic feature related to ALS. In addition, we were able to impute RNA expression from these image embeddings, in a way that elucidates molecular differences between mutants and wild-type cells. Finally, predictors leveraging these embeddings are able to distinguish between mutant and wild-type both within and across donors, defining cellular, ML-derived disease models for diverse fALS mutations. These disease models are the foundation for a novel screening approach to discover disease-modifying targets for familial ALS.

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Section: Discussionmentioning

confidence: 99%

Deep Learning Analysis on Images of iPSC-derived Motor Neurons Carrying fALS-genetics Reveals Disease-Relevant Phenotypes

Atmaramani,

Dreossi,

Ford

et al. 2024

Preprint

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“…While there are image-based algorithms and ML tools that enable neuronal segmentation, cell tracing, and identification of neurons, single neuron analyses remain difficult [4][5][6][7][8][9] . aNNs make an ideal choice to overcome limitations in the existing tools and have been implemented in similar contexts [10][11][12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Classification of iPSC-Derived Cultures Using Convolutional Neural Networks to Identify Single Differentiated Neurons for Isolation or Measurement

Patel,

Mohammed Ali,

Kaushik

et al. 2023

Preprint

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Understanding neurodegenerative disease pathology depends on a close examination of neurons and their processes. However, image-based single-cell analyses of neurons often require laborious and time-consuming manual classification tasks. Here, we present a machine learning approach leveraging convolutional neural network (CNN) classifiers that have the capability to accurately identify various classes of neuronal images, including single neurons. We developed the Single Neuron Identification Model 20-Class (SNIM20) which was trained on a dataset of induced pluripotent stem cell (iPSC)-derived motor neurons, containing over 12,000 images from 20 distinct classes. SNIM20 is built in TensorFlow and trained on images of differentiated iPSC cultures stained for nuclei and microtubules. This classifier demonstrated high predictive accuracy (AUC = 0.99) for distinguishing single neurons. Additionally, the 2-stage training framework can be used more broadly for cellular classification tasks. A variation was successfully trained on images of a human osteosarcoma cell line (U2OS) for single-cell classification (AUC = 0.99). While this framework was primarily designed for single-cell microraft-based identification and capture, it also works with cells in standard plate formats. We additionally explore the impact of specific fluorescent channels and brightfield images, class groupings, and transfer learning on the quality of the classification. This framework can both assist in high throughput neuronal or cellular identification and be used to train a custom classifier for the user’s needs.

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Towards an integrated approach for understanding glia in Amyotrophic Lateral Sclerosis

Majewski,

Klein,

Boillée

et al. 2024

Glia

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Substantial advances in technology are permitting a high resolution understanding of the salience of glia, and have helped us to transcend decades of predominantly neuron‐centric research. In particular, recent advances in ‘omic’ technologies have enabled unique insights into glial biology, shedding light on the cellular and molecular aspects of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we review studies using omic techniques to attempt to understand the role of glia in ALS across different model systems and post mortem tissue. We also address caveats that should be considered when interpreting such studies, and how some of these may be mitigated through either using a multi‐omic approach and/or careful low throughput, high fidelity orthogonal validation with particular emphasis on functional validation. Finally, we consider emerging technologies and their potential relevance in deepening our understanding of glia in ALS.

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Image‐based deep learning reveals the responses of human motor neurons to stress and VCP‐related ALS

Cited by 9 publications

References 64 publications

Deep Learning Analysis on Images of iPSC-derived Motor Neurons Carrying fALS-genetics Reveals Disease-Relevant Phenotypes

Deep Learning Analysis on Images of iPSC-derived Motor Neurons Carrying fALS-genetics Reveals Disease-Relevant Phenotypes

Classification of iPSC-Derived Cultures Using Convolutional Neural Networks to Identify Single Differentiated Neurons for Isolation or Measurement

Towards an integrated approach for understanding glia in Amyotrophic Lateral Sclerosis

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