Research News

Genetic Lineage Tracing Clarifies Cellular Origins of Resident Macrophages in Developing Heart

Source: Time: 2022-04-29

In a study published in Journal of Cell Biology, Dr. ZHOU Bin's team from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences /School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, reported the cellular origins of cardiac macrophages in the developing heart, by using a series of lineage tracing systems.

Cardiac macrophages are essential for cardiac remodeling during homeostasis and inflammation. The origins of cardiac macrophages in the developing heart remain controversial. The mainstream view holds that tissue-resident macrophages are mainly derived from the hemogenic endothelium (HE) of yolk sac (YS) and aorta-gonad-mesonephros (AGM) through endothelial to hematopoietic transition (EHT) during primitive, “transient” definitive, and definitive hematopoiesis, respectively.

Recent studies have suggested that the endocardium, labeled by Nkx2.5-Cre and Nfatc1-Cre genetic tools, as a new hemogenic endothelium (HE) contributes to transient definitive hematopoiesis in the developing heart. However, the specificity of these tools needs to be further clarified. The Nkx2.5-Cre was subsequently found to be non-specific to endocardium, as it also targets the HE of YS and AGM.

In this study, the researchers generated three Nfatc1 genetic tools, Nfatc1-ires-CreNfatc1-2A-DreNfatc1-2A-CreER, and further demonstrated that the Nfatc1 was also not a specific marker for endocardium. The Nfatc1 is broadly expressed in the HE of YS and AGM, and circulating blood cells such as macrophages and monocytes, which could interfere with the endocardial tracing results. By using two new Cre drivers that target endocardium, Mef2c-AHF-Cre and Npr3-CreER, the researchers revealed that the endocardial cells minimally contributed to cardiac macrophages and circulating blood cells.

Specifically, the researchers generated a new Cdh5-2A-CreER knock-in line, which could efficiently and specifically label endothelial cells after tamoxifen treatment. Through temporally targeting endothelium by 4-hydroxytamoxifen administration at E7.5 or E10.5, they selectively captured the hematopoietic output of the HE of YS and AGM, respectively. Fate mapping data showed that cardiac macrophages were mostly derived from primitive and “transient” definitive hematopoiesis in the YS with some being generated from definitive hematopoiesis in the AGM region.

This study clarifies the developmental origins of cardiac macrophages, which provide new insights into cardiac development, pathogenesis and regeneration.