Elucidating the Mechanisms by which Macrophages and their TAM Receptors Promote Cardiac Regeneration

Project: Research project

Project Details

Description

The prevalence of post-myocardial infarction (MI) heart failure is steadily increasing across the United States. One of the greatest challenges for the treatment of patients who have suffered an MI is the inability of the adult human heart to regenerate after ischemic injury. Current therapeutic strategies have primarily focused on stem cell-based approaches to replenish depleted cardiomyocytes. Recent clinical trials, however, have yet to register a significant impact of these therapies on cardiac function, thus necessitating novel and creative strategies to regenerate the injured myocardium.
Innate immune cells are required for both cardiac development and regeneration. Specifically, ablation of neonatal cardiac macrophages impairs cardiac regeneration as seen by diminished remuscularization and revascularization of the myocardium. Therefore, the objective of this proposal is to identify the underlying cellular and molecular mechanisms by which neonatal macrophages coordinate mammalian cardiac regeneration.
Among the many molecules that influence macrophage function, the TAM (Tyro3, Axl, MerTK) family of tyrosine kinase receptors are emerging as exciting therapeutic targets for heart disease. This proposal hypothesizes that MerTK is required to program distinct neonatal cardiac MFs to secrete pro-regenerative mediators to induce neonatal cardiomyocyte proliferation. This hypothesis will be interrogated using genetic manipulations of MerTK in neonatal mice after MI. Heart regeneration will be determined by the degree of fibrosis, the induction of cardiomyocyte proliferation, and the recovery of cardiac function as seen by echocardiography. Additionally, single-cell transcriptomics of cardiac macrophages before and after cardiac injury will unveil MerTK-dependent mechanisms that neonatal cardiac macrophages utilize to coordinate regeneration. These findings will be validated to confirm neonatal macrophage secrete mitogens to induce cardiomyocyte proliferation.
Overall, the proposed study will have broad implications for how innate immune cells and their receptors impact macrophage reprogramming and function during cardiac regeneration. This proposal will also identify novel mechanisms for cardiomyocyte proliferation, establishing the foundation for potential innovative therapeutic strategies to induce cardiac regenerative pathways in humans, alleviating the burden of post-MI heart failure on public health.
StatusActive
Effective start/end date4/1/213/31/23

Funding

  • American Heart Association (829400)

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