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Updated: Jul 3, 2026
Single Cell Transcriptional Profiling of Adult Mouse Cardiomyocytes
Published on: December 28, 2011
Multiscale mapping of transcriptomic signatures for cardiotoxic drugs
Jens Hansen1,2, Yuguang Xiong3,4, Mustafa M Siddiq3,4
1Mount Sinai Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. jens.hansen@mssm.edu.
Abstract:
Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects. Cellular pathways affected by cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to published single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Integration of transcriptomic outlier analysis with whole genomic sequencing of our six cell lines enables us to correctly reidentify a genomic variant causally linked to anthracycline-induced cardiotoxicity and predict genomic variants potentially associated with TKI-induced cardiotoxicity. We conclude that mRNA expression profiles when integrated with publicly available genomic, pathway, and single cell transcriptomic datasets, provide multiscale signatures for cardiotoxicity that could be used for drug development and patient stratification.
Insights
Gene expression profiles reveal mechanisms of drug-induced cardiotoxicity from tyrosine kinase inhibitors (TKIs). This research aids in developing safer drugs and stratifying patients for personalized medicine.
Area of Science:
- Cardiovascular Toxicology
- Genomics
- Transcriptomics
Background:
- Drug-induced cardiotoxicity is a significant concern in pharmaceutical development.
- Tyrosine kinase inhibitors (TKIs) are widely used but can pose cardiovascular risks.
- Understanding the molecular mechanisms of TKI cardiotoxicity is crucial for drug safety.
Purpose of the Study:
- To identify gene expression signatures associated with cardiotoxicity induced by FDA-approved TKIs.
- To investigate the cellular pathways affected by cardiotoxic TKIs in human cardiomyocytes.
- To integrate transcriptomic data with genomic information for predicting cardiotoxicity.
Main Methods:
- Utilized bulk transcriptomic profiling of human induced-pluripotent-stem-cell-derived cardiomyocytes.
- Employed singular value decomposition to identify drug-selective expression patterns.
- Integrated transcriptomic outlier analysis with whole-genome sequencing.
Main Results:
- Identified affected cellular pathways including energy metabolism, contractile function, and extracellular matrix dynamics.
- Demonstrated that TKI responses can occur in both cardiomyocytes and fibroblasts.
- Successfully reidentified a known cardiotoxicity-linked genomic variant and predicted novel ones.
Conclusions:
- mRNA expression profiles, when integrated with genomic and single-cell data, provide multiscale signatures for cardiotoxicity.
- These signatures can inform drug development and patient stratification strategies.
- This approach offers a comprehensive method for assessing drug-induced cardiotoxicity.
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