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Updated: Sep 15, 2025
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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
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Advanced Cardiac Organoid Model for Studying Doxorubicin-Induced Cardiotoxicity
Xian Wu1, Savanna Williams1, Jacques Robidoux1
1Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC, 27834, United States.
Biorxiv : the Preprint Server for Biology
|July 14, 2025
Summary
This study developed a new cardiac organoid model using self-secreted extracellular matrix (ECM) for mature heart cells. This advanced model improves accuracy in assessing drug cardiotoxicity, aiding heart disease research.
Area of Science:
- Biomedical Engineering
- Cardiovascular Research
- Toxicology
Background:
- Cardiac organoids are limited by immature cardiomyocytes and inadequate extracellular matrices (ECM), hindering physiological relevance and scalability.
- Current models fail to replicate natural heart tissue's biochemical and mechanical properties, leading to impaired structural integrity and mass production challenges.
- Existing ECM substitutes impede high-throughput screening for drug toxicology.
Purpose of the Study:
- To develop an advanced cardiac organoid model that overcomes limitations of cardiomyocyte immaturity and ECM inadequacy.
- To create a physiologically relevant in vitro platform for studying heart disease mechanisms and drug responses.
- To enable accurate assessment of cardiotoxicity using a mature cardiomyocyte-integrated, ECM-self-secreting organoid system.
Main Methods:
- Developed an ECM-free cardiac organoid model utilizing fibroblast-driven ECM self-secretion with mature cardiomyocytes.
- Characterized cardiomyocyte maturity using immunostaining (cTNT, MYL2) and gene expression analysis.
- Investigated doxorubicin cardiotoxicity, assessing structural changes (size, collagen deposition) and functional impairments (contraction rate, beating synchrony).
Main Results:
- The novel organoid model demonstrated physiologically relevant tissue architecture and function.
- Doxorubicin treatment in organoids resulted in reduced size, increased collagen deposition, decreased contraction rate, and disrupted synchronous beating.
- In 2D cultures, doxorubicin induced fibroblast activation, endothelial-to-mesenchymal transition, and cardiomyocyte cytotoxicity.
Conclusions:
- Fibroblast-driven ECM self-secretion is crucial for advancing cardiac organoid models towards greater physiological relevance.
- The developed organoid system provides a more accurate platform for cardiotoxicity assessment compared to conventional models.
- This approach enhances the utility of cardiac organoids for drug safety evaluation and cardiac disease modeling.
