Abstract

Heart failure and ischemic heart disease represent the most common causes of death among cancer survivors. With the tremendous progress in last few decades that empowered early cancer diagnosis and treatment, the population of cancer survivors has been rapidly growing and by 2040, the number is projected to be 26 million. However, despite extensive studies on chemotherapies, there exists a limited understanding of how exposure to chemotherapy reagents impacts heart function in the long term. Moreover, while the roles of immune landscape in heart diseases have recently been revealed, how chemotherapy reagents influence the cardiac immune cells is poorly understood. In this thesis, I investigated the influence of chemotherapy reagents on the cardiac macrophage population, which is the predominant immune cell type in the heart at steady state. Using experimental mice, immunostaining, flow cytometry, and in vitro cell culture experiments, I found carboplatin, a platinum-based DNA damaging drug, selectively depleted cardiac resident macrophages while bone-marrow derived cardiac macrophages survived. The selective depletion effect is due to overactivated DNA-damage response in combination with an incompetent DNA damage repair capacity in cardiac resident macrophages. Carboplatin leads to activation of p53 signaling disproportionally in the embryonic-derived cardiac resident macrophages, causing necroptosis and apoptosis in cardiac resident macrophages. Additionally, resident macrophages in the liver and the lung also demonstrated higher vulnerability to carboplatin. To study the long-term effect of carboplatin on the cardiac immune landscape and pathogenesis, carboplatin treated mice were followed during a four-week recovery period. Genetic lineage tracing, transcriptomic profiling, and functional studies revealed that recruited monocytes progressively reconstitute the cardiac resident macrophage compartment but were transcriptionally distinct from embryonic-derived cardiac resident macrophages. When exposed to hypertensive heart injury or ischemia-reperfusion injury, the reshaped resident-like macrophages conferred protection, evidenced by less cardiac fibrosis, mitigated cardiomyocyte hypertrophy, and preserved cardiac function. Mechanistically, these monocyte-derived resident-like cardiac macrophages are primed through a type-I interferon response that suppressed cardiac inflammation and attenuated adverse ventricular remodeling. Collectively, these findings uncover profound effects of chemotherapeutics on the cardiac immune landscape and highlight a type-I interferon dependent pathway in cardiac macrophages that protects the heart from subsequent adverse remodeling.

Committee Chair

Kory Lavine

Committee Members

David DeNardo; David Ornitz; Nima Mosammaparast; Sumanth Prabhu

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

6-16-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-3042-7537

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