KDR Identifies a Conserved Human and Murine Hepatic Progenitor and Instructs Early Liver Development

Understanding the fetal hepatic niche is essential for optimizing the generation of functional hepatocyte-like cells (hepatic cells) from human embryonic stem cells (hESCs). Here, we show that KDR (VEGFR2/FLK-1), previously assumed to be mostly restricted to mesodermal lineages, marks a hESC-derived hepatic progenitor. hESC-derived endoderm cells do not express KDR but, when cultured in media supporting hepatic differentiation, generate KDR+ hepatic progenitors and KDR− hepatic cells. KDR+ progenitors require active KDR signaling both to instruct their own differentiation into hepatic cells and to non-cell-autonomously support the functional maturation of cocultured KDR− hepatic cells. Analysis of human fetal livers suggests that similar progenitors are present in human livers. Lineage tracing in mice provides in vivo evidence of a KDR+ hepatic progenitor for fetal hepatoblasts, adult hepatocytes, and adult cholangiocytes. Altogether, our findings reveal that KDR is a conserved marker for endoderm-derived hepatic progenitors and a functional receptor instructing early liver development. •KDR is a functional receptor for human hepatic progenitors•KDR progenitors differentiate to functional hepatic cells supporting HCV infection•KDR progenitors are supportive cells for the maturation of committed hepatic cells•KDR progenitors contribute to hepatoblasts, hepatocytes, and cholangiocytes in vivo The receptor KDR (VEGFR2), normally associated with mesoderm derivatives, identifies an endoderm-derived hepatic progenitor in hESCs that is also present in fetal mouse and human liver.