Single cell transcriptomics reveals a signaling roadmap coordinating endoderm and mesoderm lineage diversification during foregut organogenesis

Visceral organs, such as the lungs, stomach, liver and pancreas, derive from the fetal foregut through a series of inductive interactions between the definitive endoderm (DE) epithelium and the surrounding splanchnic mesoderm (SM) . This foregut patterning, which occurs between embryonic day (E) 8.5 and E9.5 in the mouse embryo, equivalent to 17-23 days of human gestation, defines the landscape of the thoracic cavity and disruptions in this process can lead to severe congenital defects. While patterning of the endoderm lineages has been fairly well studies, the SM which is known to provide many paracrine factors required for organogeneis is virtually unstudied . In particular we lack a comprehensive understanding of the molecular nature of SM regional identity, the mechanisms by which SM signaling boundaries are established, the role of the epithelium in SM patterning and how SM and DE lineages are dynamically coordinated during organogenesis. Here we used single cell transcriptomics to generate a high-resolution expression map of the embryonic mouse foregut. This uncovered an unexpected diversity in SM progenitors that developed in close register with the organ-specific epithelium. These data allowed us to infer a spatial and temporal signaling roadmap of the combinatorial endoderm-mesoderm interactions that orchestrate foregut organogenesis. We validated key predictions with mouse genetics, showing importance of epithelial signaling in mesoderm patterning. Finally, we leveraged the signaling road map to generate different SM subtypes from human pluripotent stem cells (hPSCs), which previously have been elusive.