biostudies-literatureLupu IEBritish Heart FoundationVetenskapsrådetOxford University | John Fell Fund, University of Oxford (John Fell OUP Research Fund)Deutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft (German Research Foundation)Vetenskapsrådet (Swedish Research Council)BHF Centre of Research Excellence, Oxford (BHF Centre of Research Excellence in Oxford)Oxford University | John Fell Fund, University of OxfordKnut och Alice Wallenbergs StiftelseKnut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)BHF Centre of Research Excellence, OxfordWellcome Trust45-63https://www.ebi.ac.uk/biostudies/studies/S-EPMC11738995biostudies-literatureUnknown4(1)During embryogenesis, endothelial cells (ECs) are generally described to arise from a common pool of progenitors termed angioblasts, which diversify through iterative steps of differentiation to form functionally distinct subtypes of ECs. A key example is the formation of lymphatic ECs (LECs), which are thought to arise largely through transdifferentiation from venous endothelium. Opposing this model, here we show that the initial expansion of mammalian LECs is primarily driven by the in situ differentiation of mesenchymal progenitors and does not require transition through an intermediate venous state. Single-cell genomics and lineage-tracing experiments revealed a population of paraxial mesoderm-derived Etv2⁺Prox1⁺ progenitors that directly give rise to LECs. MorphoNature cardiovascular researchDirect specification of lymphatic endothelium from mesenchymal progenitors.PMC117389952020-0269431460824218561/Z/19/ZRE/13/1/301812018.02180011784Godwin JLahmann IKirschnick NZobel TVanhollebeke MJones GWeischer SLupu IESchoofs HAlitalo KMakinen TGrainger DEStone OAMartinez-Corral IRiley PRZhao EForrow AKiefer FfalseDirect specification of lymphatic endothelium from mesenchymal progenitors.During embryogenesis, endothelial cells (ECs) are generally described to arise from a common pool of progenitors termed angioblasts, which diversify through iterative steps of differentiation to form functionally distinct subtypes of ECs. A key example is the formation of lymphatic ECs (LECs), which are thought to arise largely through transdifferentiation from venous endothelium. Opposing this model, here we show that the initial expansion of mammalian LECs is primarily driven by the in situ differentiation of mesenchymal progenitors and does not require transition through an intermediate venous state. Single-cell genomics and lineage-tracing experiments revealed a population of paraxial mesoderm-derived Etv2⁺Prox1⁺ progenitors that directly give rise to LECs. Morpho2025-01-01T00:00:00Z2025 Jan2026-06-02T20:12:22.269Z2026-04-20T03:10:02.95ZS-EPMC117389953974745410.1038/s44161-024-00570-5