Endoderm Generates Endothelial Cells during Liver Development

TLDR

Organogenesis relies on the expansion of the embryonic vascular plexus that migrates into developing organs via angiogenesis, and mesodermal progenitors are traditionally thought to generate endothelial cells for vasculogenesis and organ angiogenesis. In human and mouse embryonic stem cell models, KDR⁺FOXA2⁺ endoderm cells generated during hepatic differentiation were shown to differentiate into functional endothelial cells. The study demonstrates that a subset of endothelial cells in the developing liver originates from FOXA2⁺ endoderm‑derived hepatoblast progenitors expressing KDR, and lineage tracing in mice confirms that FOXA2⁺ cells give rise to CD31⁺ endothelial cells that integrate into the fetal liver vasculature.

Abstract

Organogenesis requires expansion of the embryonic vascular plexus that migrates into developing organs through a process called angiogenesis. Mesodermal progenitors are thought to derive endothelial cells (ECs) that contribute to both embryonic vasculogenesis and the subsequent organ angiogenesis. Here, we demonstrate that during development of the liver, which is an endoderm derivative, a subset of ECs is generated from FOXA2+ endoderm-derived fetal hepatoblast progenitor cells expressing KDR (VEGFR2/FLK-1). Using human and mouse embryonic stem cell models, we demonstrate that KDR+FOXA2+ endoderm cells developing in hepatic differentiation cultures generate functional ECs. This introduces the concept that ECs originate not exclusively from mesoderm but also from endoderm, supported in Foxa2 lineage-tracing mouse embryos by the identification of FOXA2+ cell-derived CD31+ ECs that integrate the vascular network of developing fetal livers.