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

Highlights

• A non-venous cell source partially contributes to ventral heart lymphatic endothelium

• Non-venous heart lymphatics originate from SHF-derived arterial sub-mesothelial cells

• Elimination of SHF-derived lymphatics abrogates ventral heart lymphatic development

• Regionalized epicardial retinoic acid production modulates cardiac lymphangiogenesis

Summary

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.