Research

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Myocardial infarction (MI) is a leading cause of death worldwide, yet establishment of therapeutic strategies remains a critical challenge. During a heart attack, cardiac macrophages play a critical role in both the inflammatory response and tissue repair processes. They are categorized into two main types based on their ontogeny: cardiac resident macrophages (CRMs) that arise from embryonic origin and inflammatory monocyte-derived macrophages (MDMs) originating from the bone marrow during adulthood. A balance between CRMs and MDMs is necessary for optimal heart repair, highlighting the importance of understanding their differences. We have shown depletion of CRMs leads to increased interstitial fibrosis, potentially contributing to infarct expansion and decreased cardiac function. Thus, enhancing the local expansion of CRM populations is critical to improve cardiac repair and limit adverse remodeling. Interestingly, different macrophage subsets appear to depend on unique stromal sources of growth factors for their survival and polarization, suggesting that defined cell-cell communication networks are key to determining macrophage subset expansion. However, the local niche and stromal-macrophage interactions in the heart are currently unexplored. Our lab aims to understand the specific roles and interactions of macrophage subsets and cardiac stromal cells in the context of MI for translation into improved therapeutic strategies for heart attack patients.

Macrophages are a heterogenous population of immune cells found in tissues throughout the body. Single cell RNA sequencing (scRNA-seq) is a powerful tool to understand cellular heterogeneity within a tissue of interest and profile transcriptional changes and cellular phenotype in response to different stimuli. Our lab uses scRNA-seq to profile macrophage subsets in cardiac and skeletal muscle in the setting of injury to determine macrophage subset identity at the single cell level and characterize how these subsets change to orchestrate tissue repair and elucidate mechanisms by which they mediate inflammation and regeneration. This high-dimensional approach allows us to apply tools to create unsupervised single-cell trajectories and assess ligand-receptor interactions to determine subset plasticity and provide insight into subset function and intercellular communication, which can then be tested in vivo. 

Skeletal muscle regeneration is essential for maintaining healthy muscle function with disease, injury, and aging. Macrophages play a vital role in the regenerative process via pro and anti-inflammatory cytokines that act on the local tissue. The literature surrounding macrophage recruitment post-injury in muscle has primarily focused on monocytes recruited from the blood and infiltrating the tissue, where they differentiate into macrophages. These recruited macrophages are traditionally characterized into pro-inflammatory (M1) and anti-inflammatory (M2) populations. Recent discoveries using genetic fate mapping and single-cell RNA sequencing have aided in discovering distinct tissue-resident macrophage (TRM) populations consistent across various tissues. However, skeletal muscle macrophages have yet to be defined using these advancements. The M1/M2 classification system is an oversimplification of complex in vivo interactions and disregards the role of TRMs. We aim to determine the functional role of TRMs in skeletal muscle. We hypothesize that TRMs expand in regenerating muscle to promote reparative functions. First, we will use genetic fate mapping to track resident macrophages following muscle injury. The depletion of resident macrophages will follow this to determine the loss of function. Additionally, we will track recruited macrophages through other mouse models to better define these populations. Overall, we aim to understand better the role of macrophages in muscle regeneration to help generate therapeutic strategies for improved age-related muscle degeneration and maintenance of muscle function.