Cell-free DNA as a potential biomarker of differentiation and toxicity in cardiac organoids

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Abstract

Cell-free DNA (cfDNA) present in the bloodstream or other bodily fluids holds potential as a non-invasive diagnostic for early disease detection. However, it remains unclear what cfDNA markers might be produced in response to specific tissue-level events. Organoid systems present a tractable and efficient method for screening cfDNA markers. However, research investigating the release of cfDNA from organoids is limited. Here, we present a scalable method for high-throughput screening of cfDNA from cardiac organoids. We demonstrate that cfDNA is recoverable from cardiac organoids, and that cfDNA release is highest early in differentiation. Intriguingly, we observed that the fraction of cell-free mitochondrial DNA appeared to decrease as the organoids developed, suggesting a possible signature of cardiac organoid maturation, or other cardiac growth-related tissue-level events. We also observe alterations in the prevalence of specific genomic regions in cardiac organoid-derived cfDNA at different timepoints during growth. In addition, we identify cfDNA markers that were increased upon addition of cardiotoxic drugs, prior to the onset of tissue demise. Together, these results indicate that cardiac organoids may be a useful system towards the identification of candidate predictive cfDNA markers of cardiac tissue development and demise.

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All data generated or analysed during this study are included in the manuscript and supporting file

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Brian Silver

National Institute of Environmental Health Sciences, Research Triangle Park, United States

Competing interests
The authors declare that no competing interests exist.
Kevin Gerrish

National Institute of Environmental Health Sciences, Research Triangle Park, United States

Competing interests
The authors declare that no competing interests exist.
Erik Tokar

National Institute of Environmental Health Sciences, Research Triangle Park, United States

For correspondence
erik.tokar@nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1668-2830

Funding

National Institutes of Health (ES103378-01)

Erik Tokar

National Institutes of Health (ES102546)

Kevin Gerrish

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.