First blood: the endothelial origins of hematopoietic progenitors

Angiogenesis. 2021 May;24(2):199-211. doi: 10.1007/s10456-021-09783-9. Epub 2021 Mar 30.


Hematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.

Keywords: EndoHT; Endothelium; Erythro-myeloid progenitor; Fetal liver; Hematopoiesis; Hematopoietic stem cell; Tissue‐resident macrophage; Yolk sac.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cell Differentiation / radiation effects*
  • Cell Lineage / physiology*
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Endothelium / cytology
  • Endothelium / embryology*
  • Hematopoiesis / physiology*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Humans