Abstract
SummaryEndothelial 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.
Highlights
During the iterative process of differentiation, intrinsic and extrinsic cues establish heterogeneity at the cell, organ, and system level
Paraxial Mesodermal Cells Contribute to the Cardinal Vein and Developing Lymphatics Genetic lineage tracing has demonstrated the presence of a multipotent progenitor population in the mouse dermomyotome that is marked by the expression of PAX3 and MYF5 (Figure S1A), and gives rise to skeletal muscle and endothelium (Buckingham and Rigby, 2014)
lymphatic ECs (LECs) progenitors are known to differentiate from the dorsolateral wall of the cardinal vein under the transcriptional control of SOX18, COUPTFII, and PROX1 (Francois et al, 2008; Srinivasan et al, 2007; You et al, 2005; Wigle and Oliver, 1999), and previous studies have reported a contribution of somitic cells to the lymphatic endothelium in avian embryos (Wilting et al, 2006; He et al, 2003; Schneider et al, 1999)
Summary
During the iterative process of differentiation, intrinsic and extrinsic cues establish heterogeneity at the cell, organ, and system level. Multiple cellular origins for endothelial cells (ECs) have been described (Plein et al, 2018; Reischauer et al, 2016; Klotz et al, 2015; Stanczuk et al, 2015; Nguyen et al, 2014; Wilting et al, 1995), the impact of cell lineage on EC diversification is poorly understood. The prevailing view is that tissue-derived signals, coupled to vessel subtype-specific transcriptional networks, establish molecular and functional heterogeneity as ECs invade different organs and tissues (Potente and Ma€kinen, 2017). Transplantation experiments in avian embryos showed that while PXM-derived ECs contribute to the cardinal vein, wing bud, and perineural vascular plexus, they are unable to invade the visceral organs and are excluded from the ventral wall of the dorsal aorta (Pardanaud et al, 1996), suggesting that ECs from divergent sources may possess unique functional and molecular properties
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