M Tavian

Angiotensin-converting enzyme (CD143) specifies emerging lympho-hematopoietic progenitors in the human embryo

Adult-type lympho-myeloid hematopoietic progenitors are first generated in the aorta-gonad-mesonephros region between days 27 and 40 of human embryonic development, but an elusive blood forming potential is present earlier in the underlying splanchnopleura. In the present study, we show that angiotensin-converting enzyme (ACE, also known as CD143), a recently identified cell-surface marker of adult human hematopoietic stem cells, is already expressed in all presumptive and developing blood-forming tissues of the human embryo and fetus: para-aortic splanchnopleura, yolk sac, aorta-gonad-mesonephros, liver, and bone marrow (BM). Fetal liver and BM-derived CD34(+)ACE(+) cells, but not CD34(+)ACE(-) cells, are endowed with long-term culture-initiating cell potential and sustain multilineage hematopoietic cell engraftment when transplanted into NOD/SCID mice. Furthermore, from 23-26 days of development, ACE expression characterizes rare CD34(-)CD45(-) cells concentrated in the hemogenic portion of the para-aortic splanchnopleura. ACE(+) cells sorted from the splanchnopleura generated colonies of hematopoietic cells more than 40 times more frequently than ACE(-) cells. These data suggest that, in addition to being a marker of adult human hematopoietic stem cells, ACE identifies embryonic mesodermal precursors responsible for definitive hematopoiesis, and we propose that this enzyme is involved in the regulation of human blood formation.

Origin of the hematopoietic system in the human embryo

The continuous generation of blood cells throughout life relies on the existence of hematopoietic stem cells (HSC) generated during embryogenesis. Given the importance of HSC transplantation in cell‐based therapeutic approaches, considerable efforts have been made toward understanding the developmental origins of embryonic HSC. Adult‐type HSC are first generated in the aorta‐gonad‐mesonephros (AGM) region between days 27 and 40 of human embryonic development, but an elusive blood‐forming potential is present earlier in the underlying splanchnopleura. It is relatively well accepted that the HSC emerge in the AGM through a hemogenic endothelium, but the direct precursor of this cell type remains to be clearly identified. This review is intended to summarize the recent advances made to understand the origins of hematopoietic stem cells in the early human embryo. In addition, we discuss in detail the discovery of the angiotensin‐converting enzyme (ACE) as a novel marker of human HSC and of prehematopoietic precursors inside the embryo.