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Conditional lineage ablation to model human diseases
1Section of Myocardial Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Abstract:
Cell loss contributes to the pathogenesis of many inherited and acquired human diseases. We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline-responsive promoters. As an example of this approach, we targeted expression of DTA to the hearts of adult mice to model structural abnormalities commonly observed in human cardiomyopathies. Induction of DTA expression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated-perfused transgenic hearts demonstrated a strikingly high incidence of spontaneous and inducible ventricular tachycardia. Affected mice showed marked perturbations of cardiac gap junction channel expression and localization, including a subset with disorganized epicardial activation patterns as revealed by optical action potential mapping. These studies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicability for studies of disease pathogenesis.
Insights
Researchers developed a novel system for targeted cell ablation in mice using diphtheria toxin A (DTA) gene expression. This method effectively models human cardiomyopathies, revealing insights into cardiac cell loss and arrhythmias.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Genetics
Background:
- Cell loss is a key factor in numerous human diseases.
- Understanding cell loss mechanisms is crucial for disease pathology.
- Existing models may not fully capture complex disease processes.
Purpose of the Study:
- To develop a versatile system for conditional cell ablation in mice.
- To model human cardiomyopathies using targeted cardiac cell loss.
- To investigate the mechanisms underlying disease-induced arrhythmias.
Main Methods:
- Utilized tetracycline-responsive promoters to regulate diphtheria toxin A (DTA) gene expression.
- Targeted DTA expression to the hearts of adult mice.
- Assessed cardiac structure, function, and electrophysiology in transgenic mice.
Main Results:
- Induced cell loss, fibrosis, and chamber dilatation in mouse hearts.
- Observed a high incidence of spontaneous and inducible ventricular tachycardia.
- Identified significant alterations in cardiac gap junction expression and localization.
Conclusions:
- Conditional lineage ablation is a powerful tool for disease modeling.
- The developed system provides insights into arrhythmogenesis in cardiomyopathies.
- This approach has broad applicability for studying various disease pathologies.