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Updated: Jan 7, 2026
Assessing Stem Cell DNA Integrity for Cardiac Cell Therapy
Published on: January 25, 2019
DNA-damaging chemotherapy reshapes cardiac-resident macrophage composition and function
Ruijun He1, Farid F Kadyrov1, Andrew L Koenig1
1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
Heart failure and ischemic heart disease represent prevalent causes of death among cancer survivors. Despite extensive use of conventional chemotherapies, a limited understanding of how these agents affect the cardiac immune landscape exists. Using mouse models, we show that DNA-damaging agents selectively deplete cardiac-resident macrophages through activation of p53 signaling and resultant necroptosis and apoptosis. Genetic lineage tracing, transcriptomic profiling, and functional studies revealed that recruited monocytes progressively reconstitute the cardiac-resident macrophage compartment, were transcriptionally distinct from embryonic-derived cardiac-resident macrophages, and conferred protection from subsequent hypertensive and ischemic cardiac injury in mice. Monocyte-derived resident-like cardiac macrophages suppressed inflammation and attenuated adverse myocardial remodeling through a type I interferon-dependent mechanism. Collectively, these findings highlight unrecognized effects of DNA-damaging chemotherapies on the cardiac immune landscape and shed light on our understanding of monocyte plasticity and resident macrophage dynamics.
Insights
DNA-damaging chemotherapy depletes heart macrophages, but recruited monocytes rebuild the cardiac immune system, offering protection against heart injury. This study reveals chemotherapy
Area of Science:
- Cardiovascular immunology
- Cancer therapy side effects
- Macrophage biology
Background:
- Heart failure and ischemic heart disease are major causes of death in cancer survivors.
- Conventional chemotherapies' impact on the cardiac immune system is poorly understood.
- DNA-damaging agents are widely used in cancer treatment.
Purpose of the Study:
- To investigate the effects of DNA-damaging chemotherapies on cardiac-resident macrophages.
- To understand the mechanisms of cardiac immune system reconstitution after chemotherapy.
- To explore the protective functions of newly recruited cardiac macrophages.
Main Methods:
- Mouse models of chemotherapy exposure.
- Genetic lineage tracing to track cell origins.
- Transcriptomic profiling to analyze gene expression.
- Functional assays to assess cardiac injury and protection.
Main Results:
- DNA-damaging agents induce p53-dependent depletion of cardiac-resident macrophages via necroptosis and apoptosis.
- Recruited monocytes repopulate the cardiac macrophage compartment.
- Monocyte-derived macrophages are transcriptionally distinct from embryonic-derived macrophages.
- These monocyte-derived macrophages protect against hypertensive and ischemic cardiac injury.
- They suppress inflammation and adverse remodeling through type I interferon signaling.
Conclusions:
- DNA-damaging chemotherapies profoundly alter the cardiac immune landscape by depleting resident macrophages.
- Monocyte plasticity allows for the reconstitution of a protective cardiac macrophage pool.
- These findings enhance understanding of chemotherapy cardiotoxicity and macrophage dynamics.
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