We are focused on understanding the role myeloid cells (monocytes, macrophages, and dendritic cells) play within the myocardium during steady-state and following tissue injury. These myeloid subsets are a heterogeneous population of cells with distinct origins and functions and participate in the initial inflammatory and subsequent wound healing responses after myocardial tissue injury. Using genetic and surgical mouse models, and bioinformatics approaches, we aim to investigate how individual myeloid subsets are activated, what factors regulate their entry, persistence, and fate after entry into the myocardium.
In addition, we are identifying the contribution of each myeloid subset to the process of cardiac regeneration. We use models of hemodynamic stress (hypertension), ischemic stress (myocardial infarction) and also infective injury (viral myocarditis) in order to study the role of macrophages in tissue damage and repair.
Myocardial infarction (MI), or heart attack, is caused by a blockage in a coronary artery resulting in insufficient blood flow to the heart. An inflammatory response occurs following an MI which can lead to adverse cardiac remodeling and cardiac dysfunction. Macrophages play a key role in both the inflammatory and reparative response. Particularly, tissue-resident macrophages are critical regulators of homeostasis and immunity, yet their role in tissue repair is poorly understood. We have shown that cardiac macrophages are transcriptionally, ontogenetically and functionally heterogeneous. We are interested in understanding the heterogeneity of tissue-resident macrophages as it pertains to function in the setting of myocardial infarction. Defining pathways responsible for their specification and function will aid our ability to enhance these processes in the setting of injury and disease.
Hypertension, affecting 1 in 3 adults world-wide, is a leading cause of heart failure from maladaptive cardiac remodelling. Currently heart failure has a poorer prognosis than cancer, highlighting an unmet need for novel therapeutic approaches. The immune system participates in the sterile inflammation triggered during hypertension, however, the exact components that mediate vs protect against heart failure remains unknown. In the Epelman lab, we are interested in defining the function of relevant immune cells and mechanisms of protection during hypertensive heart disease.
Myocarditis, inflammation of the myocardium, is an important yet underappreciated cause of heart failure and acute death in individuals under 40 years of age. The most common cause of myocarditis is viral infection and there is growing evidence that the impact of viral myocarditis in the development of heart disease is underestimated. There is currently no treatment for viral myocarditis, and little is known about the pathophysiology of viral infection in the heart. Our lab aims to better understand the pathways involved in the virus-specific immune response during viral myocarditis and factors leading to better or worse cardiac outcomes.
SARS-Cov-2 and the heart
We are focused on the intersection between viral cardiac injury due to SARS-CoV-2 and other cardiac risk factors, such as hypertension and ischemic injury. We use mouse and hamster models of SARS-CoV-2 infection, genetic approaches and single cell technologies within our level 3 containment facility. As part of the Emerging & Pandemic Infectious Consortium (EPIC), our goal is to decipher mechanisms of immune cell function in viral cardiac injury: https://epic.utoronto.ca/our-mission/researchers/
We have integrated computational analyses to complement our wet lab work. We have knowledge and expertise in a number of techniques and analyses including single cell and single nuclei RNA sequencing, ATAC-seq and bulk RNA sequencing.
Single-cell RNA sequencing in particular is a powerful tool which we use to explore the transcriptional heterogeneity of immune cell populations at homeostasis and in various disease states. We use this to understand myeloid cell fates in the setting of disease. How do myeloid cells respond during injury? What are the various activation states assumed during disease? What are the roles of new cellular fates that arise? These are some of the key questions we wish to address in the setting of myocardial infarction, hypertension and viral myocarditis.
Bioengineering is a discipline that applies the engineering principles of design and analysis to biological systems and biomedical technologies, with the aim of solving health-related problems and developing tools for diagnosis, treatment, and prevention.
We leverage 3D culture platforms that mechanically and electrically resemble the human heart. We aim to investigate how tissue resident cardiac macrophages contribute to cardiac function and homeostasis.
We have several integrated translational projects that focus on the corresponding human myeloid subsets, how they are activated and how their activation state relates to myocardial function and myocardial recovery in patients following myocardial tissue injury (myocardial infarction). By focusing on how myeloid cells are activated in humans, we hope to identify pathological pathways that both identify patients who will be at high risk for developing severe cardiac dysfunction, and also identify new therapeutic targets.