Origin of the hematopoietic system in the human embryo

Abstract

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.

p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita

“…Our observed near-complete failure of definitive hematopoietic output from phenotypic hemogenic endothelium, which is restored by p53 deletion, suggests that p53 directly regulates definitive hematopoietic potential in DC cells. Hemogenic endothelium is the direct precursor to the hematopoietic stem cell (Julien et al., 2016), raising the possibility that our observations and clinical BMF may both be due to conserved mechanism(s) governed by p53. As our understanding of human definitive hemogenic endothelium improves, we will be able to better define the role of p53 in this complex developmental process.…”

Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic coculture

“…Our analyses focused, in part, on the markers CD49f and ACE, together with the known human HSC marker CD34 [53,82], all shown to enrich for the functional population of HSCs (Fig. 2).…”

“…ACE enriches for HSCs and also marks all cells in the developing embryo destined to adopt a hematopoietic fate [51][52][53]. Likewise, CD49f (also known as integrin a6) also enriches for HSCs [53,54]. 3GF reprogramming results in expanded yields of all populations of hematopoietic progenitors (in this case ACE + , CD49f + , or ACE + CD49f + cells) as compared to GGF ( Fig.…”

“…ACE enriches for HSCs and also marks all cells in the developing embryo destined to adopt a hematopoietic fate [51][52][53]. To this end, cell surface marker expression of developmental human HSC markers CD34, CD49f, and angiotensin converting enzyme (ACE) was analyzed at several time points during reprogramming.…”

Hierarchical organization of developing HSPC in the human embryonic liver

“…The first HSPCs emerge from specialized endothelial cells (EC), known as hemogenic endothelium (HE), in the aorta-gonad-mesonephros (AGM) region, migrate to the fetal liver to be massively amplified and finally reach the bone marrow (BM) their life-long residence (Ivanovs et al, 2017;Klaus and Robin, 2017;Crisan and Dzierzak, 2016;Ciau-Uitz and Patient, 2016;Julien et al, 2016;Medvinsky et al, 2011). This conversion of endothelium into HCs termed endothelial-tohematopoietic transition (EHT) has been extensively verified in various animal model (Boisset et al, 2015 andChen et al, 2011 andBertrand et al, 2010;Kissa and Herbomel, 2010;Eilken et al, 2009;Zovein et al, 2008;Fraser et al, 2002;Jaffredo et al, 1998;Nishikawa et al, 1998a) and…”