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

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Project Summary The prevalence of post-myocardial infarction (MI) heart failure is increasing across the United States, since current therapeutic strategies fail to regenerate the injured myocardium. While other organ systems exhibit the ability to regenerate after tissue injury, the adult human heart lacks this crucial capability. With the discoveries of multipotent cells and advanced culturing and differentiation techniques, studies have focused on stem cell- based therapeutic approaches to replenish depleted cardiomyocytes. Clinical trials, however, have yet to register a significant impact of these therapies on cardiac function, thus necessitating novel and creative approaches to regenerate the injured myocardium. Remarkably, innate immune cells are required for both cardiac development and regeneration. Ablation of neonatal cardiac macrophages (MΦs) impairs the regenerative response, inhibiting the remuscularization and revascularization of the myocardium. The precise molecular mechanisms, however, for the regenerative reprogramming of macrophages remain unknown. Therefore, the long-term 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 MΦ 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 MΦs to secrete pro-regenerative mediators that coordinate cardiac regeneration. This hypothesis will be interrogated using genetic manipulation of MerTK in neonatal mice after myocardial infarction. 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 MΦs before and after cardiac injury will unveil the MerTK- dependent mechanisms neonatal cardiac MΦs utilize to coordinate regeneration. These mechanisms of cardiac regeneration will be validated to confirm the regenerative functions of neonatal MΦs. Dr. Edward Thorp’s laboratory and Northwestern University provide both the expertise, facilities and necessary equipment required to thoroughly interrogate the aims of the proposal. Overall, the proposed study will have broad implications for how innate immune cells and their receptors directly execute regenerative functions. These findings may identify novel therapeutic strategies to induce cardiac regeneration in humans, alleviating the burden of post-MI heart failure on public health.