Tissue experienced resident macrophages of the perivascular niche in myocardial infarction

组织驻留巨噬细胞是体内平衡所必需的成体组织的细胞组分。在健康的心脏中，组织驻留的巨噬细胞约占总细胞的6%至8%，其功能远远超出经典的免疫监视能力。事实上，心脏驻留巨噬细胞已经涉及电传导、代谢控制或动脉和淋巴管系统的发育。在心脏损伤的情况下，包括心肌梗死，心脏驻留巨噬细胞抗纤维化，促进血管生成，并调节对损伤的炎症反应。心脏驻留巨噬细胞包括在胚胎发育期间定殖于心脏的巨噬细胞，其通过自我更新维持其水平，以及出生后通过循环前体即单核细胞更新的巨噬细胞。此外，心脏驻留巨噬细胞是异质的，并且包括由其组织下定位和特异性细胞表面标志物限定的两个主要群体：TIMD 4 +MHCII-巨噬细胞是血管周围的，而TIMD 4-MHCII+巨噬细胞定位在神经附近。总之，最近的证据表明，心脏驻留巨噬细胞的身份和功能是由其发育起源，并从他们的直接微环境，即他们居住的特定生态位的信号。研究如何建立和维持特定的心脏组织驻留巨噬细胞特性将有助于揭示心脏驻留巨噬细胞身份在多大程度上取决于长期居住在特定的生态位，而不是它们的发育起源。了解组织驻留巨噬细胞功能编程的机制与它们在心肌梗死中的作用特别相关，在心肌梗死中它们协调炎症和组织修复过程。PERIMAC项目的主要假设是，在血管周围小生境中建立时间依赖性驻留的组织驻留巨噬细胞在心脏组织中获得未受挑战的修复功能。在三个具体目标中，我们将（i）表征血管周围心脏驻留巨噬细胞的身份和起源以及印记其身份的分子信号，（ii）分析血管周围驻留巨噬细胞在缺血后心脏修复中的作用，以及（iii）破译心脏血管周围巨噬细胞修复功能的分子机制。

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.