Deep learning detects cardiotoxicity in a high-content screen with induced pluripotent stem cell-derived cardiomyocytes
Abstract
Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to detect drug-induced toxicity in vitro. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those with potential cardiotoxic liabilities in iPSC-CMs using a single-parameter score based on deep learning. Compounds demonstrating cardiotoxicity in iPSC-CMs included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks that show cardiotoxic signal in iPSC-CMs. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that may protect against diseased phenotypes and deleterious mutations.
Data availability
Our RNA-Seq data has been deposited on the Gene Expression Omnibus (GEO) database. GEO Submission (GSE172181):https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE172181
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Deep Learning Predicts Patterns of Cardiotoxicity in a High-Content Screen Using iPSC-CMsNCBI Gene Expression Omnibus, GSE172181.
Article and author information
Author details
Funding
No external funding was received for this work
Reviewing Editor
- Arduino A Mangoni, Flinders Medical Centre, Australia
Version history
- Preprint posted: March 24, 2021 (view preprint)
- Received: March 24, 2021
- Accepted: July 27, 2021
- Accepted Manuscript published: August 2, 2021 (version 1)
- Version of Record published: August 16, 2021 (version 2)
Copyright
© 2021, Grafton et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Neuroscience
- Stem Cells and Regenerative Medicine
Neural stem cells (NSCs) are multipotent and correct fate determination is crucial to guarantee brain formation and homeostasis. How NSCs are instructed to generate neuronal or glial progeny is not well understood. Here we addressed how murine adult hippocampal NSC fate is regulated and describe how Scaffold Attachment Factor B (SAFB) blocks oligodendrocyte production to enable neuron generation. We found that SAFB prevents NSC expression of the transcription factor Nuclear Factor I/B (NFIB) by binding to sequences in the Nfib mRNA and enhancing Drosha-dependent cleavage of the transcripts. We show that increasing SAFB expression prevents oligodendrocyte production by multipotent adult NSCs, and conditional deletion of Safb increases NFIB expression and oligodendrocyte formation in the adult hippocampus. Our results provide novel insights into a mechanism that controls Drosha functions for selective regulation of NSC fate by modulating the post-transcriptional destabilization of Nfib mRNA in a lineage-specific manner.
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- Stem Cells and Regenerative Medicine
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