Grant: Project Grant

Skeletal muscle is critical for locomotion, force generation, energy metabolism, and thermoregulation. As such, disruptions in muscle function and regeneration can have a profound impact on human health. During aging, and in diseases such as muscular dystrophies, muscle regeneration is compromised leading to weakened muscle, frailty, and decreased quality of life. Inflammation has been correlated with worse regeneration, however, attempts to eliminate inflammatory immune cells have led to conflicting results due to their dual role in regeneration. Thus, a lack of understanding of immune subsets present in the regenerating tissue and their diverse functions have limited progress. Our research is centred on the intersection of immunology and regenerative medicine to understand how different macrophage subsets mediates muscle regeneration, how the immune response is altered in aging, and the cellular crosstalk between macrophages, stem cells, and fibroblasts. Our group has shown tissue resident macrophages are critical for cardiac repair following a heart attack and are present in muscle tissue, however their role in muscle regeneration has yet to be determined. These are functionally different from recruited macrophages that are typically more inflammatory. Here we will use novel fate mapping and single cell-omics techniques to determine the heterogeneity and ontogeny of macrophage subsets in the injured muscle. We will define the functional role of resident and recruited macrophage subsets by specifically targeting them in a mouse model of muscle regeneration and define the cell interactomes and niche environments of each subset to identify novel mediators which we can then target. Overall, this innovative approach to understanding immune heterogeneity and the functionally diverse roles macrophage subsets play in inflammation/regeneration will allow for the development of novel immune targeted therapies to eliminate chronically inflamed tissues and promote repair.