Tissue experienced resident macrophages of the perivascular niche in myocardial infarction

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Tissue resident macrophages are cellular components of adult tissues essential to homeostasis. In the healthy heart, tissue resident macrophages represent around 6% to 8% of total cells, where their functions go well beyond classical immune surveillance abilities. Indeed, cardiac resident macrophages have been implicated in electrical conduction, control of metabolism, or development of the arterial and lymphatic vasculature. In cardiac injury contexts, including myocardial infarction, cardiac resident macrophages are anti-fibrotic, promote angiogenesis, and regulate the inflammatory response to injury. Cardiac resident macrophages comprise macrophages colonizing the heart during embryonic development maintaining their levels via self-renewal, and macrophages postnatally renewed by circulating precursors, i.e. monocytes. Cardiac resident macrophages are furthermore heterogeneous, and comprise two major populations defined by their sub-tissular localization and specific cell surface markers: TIMD4+MHCII- macrophages are perivascular, while TIMD4-MHCII+ macrophages localize near nerves. Altogether, recent evidence indicate that the identity and function of cardiac resident macrophages is dictated by their developmental origin, and by signals from their immediate microenvironment, i.e. the specific niche in which they reside. Studying how specific cardiac tissue resident macrophage characteristics are established and maintained will help to reveal to what extent cardiac resident macrophage identities are dictated by long-term residence in a specific niche, as opposed to their developmental origin. Understanding the mechanisms underlying tissue resident macrophage functional programming is of particular relevance to their role in myocardial infarction, where they orchestrate inflammatory and tissue repair processes. The main hypothesis of the PERIMAC project is that tissue resident macrophages establishing time-dependent residence in the perivascular niche acquire unchallenged reparative function in the cardiac tissue. In three specific aims, we will (i) characterize the identity and origin of perivascular cardiac resident macrophages and the molecular signals imprinting their identity, (ii) analyze the role of perivascular resident macrophages in post-ischemic cardiac repair and (iii) decipher the molecular mechanisms involved in cardiac perivascular macrophage reparative function.