A Second Heart Field-Derived Vasculogenic Niche Contributes to Cardiac Lymphatics.

The mammalian heart contains multiple cell types that appear progressively during embryonic development. Advance in determining cardiac lineage diversification has often been limited by the unreliability of genetic tracers. Here we combine clonal analysis, genetic lineage tracing, tissue transplantation, and mutant characterization to investigate the lineage relationships between epicardium, arterial mesothelial cells (AMCs), and the coronary vasculature. We report a contribution of the second heart field (SHF) to a vasculogenic niche composed of AMCs and sub-mesothelial cells at the base of the pulmonary artery. Sub-mesothelial cells from this niche differentiate into lymphatic endothelial cells and, in close association with AMC-derived cells, contribute to and are essential for the development of ventral cardiac lymphatics. In addition, regionalized epicardial/mesothelial retinoic acid signaling regulates lymphangiogenesis, contributing to the niche properties. These results uncover a SHF vasculogenic contribution to coronary lymphatic development through a local niche at the base of the great arteries.We thank Cristina Villa del Campo, Ester de la Cruz, and other members of the Torres group for stimulating discussions and suggestions. We thank members of the Microscopy, Genomics, Bioinformatics, Transgenesis, and Animal Facility CNIC units for excellent support. This work was supported by grants PGC2018-096486-B-I00 and RD16/0011/0019 (ISCIII) from the Spanish Ministry of Science, Innovation, and Universities and grant S2017/BMD3875 from the Comunidad de Madrid to M.T., grant ITN-CARDIONET-ref.289600 from EU to G.L., and by grant BFU2015-71376-R to S.O. The CNIC is supported by the Ministerio de Ciencia, Innovacio´ n y Universidades, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work was also supported by NIH grant RO1HL073402 to G.O. and by AHA grant 18CDA34110356 to X.L.S