Physics

Paraxial mesoderm

Mesoderm

Biology

Gene

Optics

Embryonic stem cell

Beam (structure)

Lymphatic system

Intermediate mesoderm

Immunology

Cell biology

Genetics

Paraxial approximation

Developmental Cell

Highlights•Lineage history is a key determinant of endothelial cell specialization•Endothelial cells arising from paraxial mesoderm preferentially form lymphatic vessels•Paraxial-mesoderm-derived endothelial cells are essential for lymphatic developmentSummaryEndothelial cells (ECs), which line blood and lymphatic vessels, are generally described to come from the lateral plate mesoderm despite experimental evidence for a broader source of origin, including the paraxial mesoderm (PXM). Current dogma suggests that following specification from mesoderm, local environmental cues establish the distinct molecular and functional characteristics of ECs in different vascular beds. Here we present evidence to challenge this view, showing that lymphatic EC fate is imprinted during transition through the PXM lineage. We show that PXM-derived cells form the lymphatic endothelium of multiple organs and tissues, with a more restricted contribution to blood vessel endothelium. By deleting Prox1 specifically in PXM-derived cells, we show that this lineage is indispensable for lymphatic vessel development. Collectively, our data establish lineage history as a critical determinant of EC specialization, a finding with broad implications for our understanding of vascular development and heterogeneity.Graphical abstract

Paraxial Mesoderm Is the Major Source of Lymphatic Endothelium