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  • Dual lineage tracing identifies intermediate mesenchymal stage for endocardial contribution to fibroblasts, coronary mural cells, and adipocytes.

Dual lineage tracing identifies intermediate mesenchymal stage for endocardial contribution to fibroblasts, coronary mural cells, and adipocytes.

The Journal of biological chemistry (2019-04-24)
Xinyan Huang, Teng Feng, Zhen Jiang, Jufeng Meng, Shan Kou, Zhengkai Lu, Weize Chen, Chao-Po Lin, Bin Zhou, Hui Zhang
ABSTRACT

Early embryonic endocardium undergoes endothelial-to-mesenchymal transition to form cardiac cushion mesenchymal cells (MCs). Embryonic endocardium also gives rise to fibroblasts, intramyocardial adipocytes, and coronary mural cells, including smooth muscle cells and pericytes, in development. Whether endocardial cells directly differentiate into fibroblasts, coronary mural cells, and adipocytes or indirectly via an intermediate stage of endocardial-derived cushion MCs remains unknown. In addition to endocardium, epicardium and neural crest also contribute to cardiac cushion MCs. Given the developmental heterogeneity of cushion MCs and the lack of specific markers for endocardial-derived cushion MCs, conventional genetic lineage tracing utilizing Cre recombinase driven by one specific regulatory element is not sufficient to examine the fates of endocardial-derived cushion MCs. Intersectional genetic targeting approaches, which combine regulatory elements from two or more genes, have been employed to increase the specificity of cell targeting. Here, we developed a dual-recombinase intersectional targeting approach using Nfatc1-Dre, Sox9-CreER, and Cre/Dre double-dependent reporter Ai66 to specifically label endocardial-derived cushion MCs. Taking advantage of intersectional lineage tracing, we found that a subset of cardiac cells including fibroblasts, coronary mural cells, and intramyocardial adipocytes in adult hearts were derived from endocardial-derived cushion MCs. Our study suggests that embryonic endocardium contributes to cushion MCs first, and then endocardial-derived cushion MCs migrate into myocardium and differentiate into fibroblasts, coronary mural cells, and adipocytes in development. Understanding developmental origins of cardiac cell lineages will provide us more insights into cardiac development, regeneration, and diseases.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Amyloid Precursor Protein Antibody, KPI Domain, serum, Chemicon®
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Anti-Sox9 Antibody, Chemicon®, from rabbit
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Anti-Actin, α-Smooth Muscle - FITC antibody, Mouse monoclonal, clone 1A4, purified from hybridoma cell culture