Cardiac resident macrophages: Spatiotemporal distribution, development, physiological functions, and their translational potential on cardiac diseases

Figures

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  Figure 1. CRMs subsets residing in different anatomical niches. (A) Macrophages in the AN. High-density CRMs in the AN control the electrical conduction of cardiomyocytes via Cx43, thus controlling the contractile function of the heart. (B) CRMs in the heart valve. CRMs within heart valves can also continue to be subdivided, with CD206+ CRMs located primarily under the endothelium at the region of coaptation, and MHCII+ CRMs located at the distal end of the aortic valve and mitral leaflets, which may be associated with valve homeostasis and repair. (C) CRMs in the right atrium. Most notably, CRMs in the right atrium show strong genetic differences from those in other chambers, but the specific physiological functions remain unclear. (D) Macrophages in the pericardial cavity. The Gata6+ CRMs in the pericardial cavity have a similar transcriptional profile with peritoneal and pleural macrophages. AN means atrioventricular node.

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  Figure 2. The changes of CRMs in life cycle, and their influences on cardiac development and aging. (A) The origin and maintenance of CRMs. Yolk sac and fetal liver-derived CRMs settle into the heart prenatally and can maintain renewal through self-proliferation. M-CSF and IL-4 can promote the proliferation of macrophages, additionally, SR-A1 binds to ligands, thereby activating c-Myc to promote CRMs proliferation. Macrophages derived from monocytes contribute relatively small to the heart at homeostasis. (B) The changes of CRMs in the life cycle. MP1 subset is the dominant group in the embryo and neonatal stage, MP4 dominates in the adult stage, MP2/3 subsets are throughout the life cycle. The tendency of MP1/2, MP3, and MP4 may be consistent with those of TLF+, CCR2+, and MHCII+ CRMs, respectively. (C) CRM's influences on cardiac development and aging. Yolk sac and fetal liver-derived CRMs promote the development of heart valves, coronary artery and lymphatic vessels, cardiomyocyte proliferation, and removal of apoptotic cells. Cardiac aging causes mitochondrial dysfunction, which eventually inhibits the reprogramming of pro-inflammatory macrophages to anti-inflammatory phenotypes,…

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  Figure 3. CRMs involve cardiac electrical conduction and their associated AF. CRMs interspersed between cardiomyocytes form a network, they are densely enriched in the AN and are at a key position for cardiomyocytes to exchange signals. They connect to cardiomyocytes via Cx43 to generate electrical conduction, which eventually converts electrical signals between heart chambers into muscle contractions. Depletion of Cx43 delays and blocks electrical conduction of the AN in mice, leading to AF. In addition, infiltrated macrophages produce inflammatory factors and result in an increased risk of AF. AF and AN mean atrial fibrillation and atrioventricular node, respectively.