Endodermal Cells Differentiate Into Endothelial Cells to Function as a Vascular Niche for Hematopoietic Stem and Progenitor Cells

Endothelial cells (ECs) line blood vessels and also serve as a niche for hematopoietic stem and progenitor cells (HSPCs). Recent data point to tissue-specific EC specialization as well as heterogeneity; however, it remains unclear how ECs acquire these properties. Here, we mapped the origin of the vascular HSPC niche in zebrafish embryos by combining live imaging-based lineage tracing and single cell transcriptomics. We identify islet1 (isl1)-expressing cells as the progenitors of the venous ECs that constitute the HSPC niche. These isl1-expressing cells surprisingly originate from the endoderm and differentiate into ECs in a process dependent on Bmp-Smad signaling and subsequent npas4l (cloche)-promoted signaling. Single cell RNA-sequencing analyses reveal that endoderm-derived ECs express a set of genes that reflects their unique origin even as they become heterogeneous. This study demonstrates that endothelial specialization in the vascular HSPC niche is determined by origin of ECs.