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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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