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Regulation of human haematopoietic stem cell self renewal

Human embryonic haematopoietic tissues. A The location of the AGM region, yolk sac, liver, vitelline and umbilical arteries and placenta in a CS 15 human embryo. The location of the amnion, eye, and upper and lower limbs are also indicated for reference. Note that HSCs at this stage are localised to the AGM region and will appear in regulation of human haematopoietic stem cell self renewal yolk sac and liver slightly later. Whole-mount antibody staining left and sagittal confocal section of the boxed area right.

The largest clusters are usually localised close to the entry of the vitelline artery. The AGM region The appearance of IAHCs on the ventral wall of the human dorsal aorta in the AGM region, reported early last century Minot, 1912marks the onset of the intra-embryonic, permanent adult haematopoietic wave in the vertebrate embryo.

Spatiotemporal analysis revealed that IAHCs emerge at CS 13 27 dpcexclusively at the floor of the embryonic dorsal aorta and disappear by CS 17 39-42 dpc Tavian et al. In the human embryo, IAHC formation covers the pre-umbilical area of the floor of the dorsal aorta and penetrates the entry to the vitelline artery Fig.

Although it is broadly accepted that IAHCs are formed from mesodermal precursors through endothelial intermediates, in the absence of direct tracking, various scenarios of IAHC formation can be considered Medvinsky et al.

Developing human IAHCs sometimes appear to penetrate through the aortic endothelial lining Tavian et al. Identification of the exact migration pathways during HSC specification in the mammalian AGM region remains one of the least explored issues in the field. The liver The liver rudiment emerges as a diverticulum from the floor of the embryonic gut at early CS 10 21 dpc.

Although direct experimental evidence is lacking, these might be the cells that progressively replace primitive erythroblasts in the human embryo bloodstream during liver colonisation from CS 13-14 30-33 dpc onwards Migliaccio et al.

The liver remains an important niche for haematopoietic differentiation and HSC expansion until birth. Although some analysis of the developing liver as the haematopoietic niche was conducted on the mouse, this issue in human remains a largely unexplored territory. For this reason, the placenta is considered to be one of the HSC sources in the mouse embryo Gekas et al. At this stage, the placenta is also a site of extensive erythroid maturation: The bone marrow The development of the definitive bone marrow niche is closely linked to the invasion of cartilaginous bone by blood vessels and bone ossification.

Vascular invasion facilitates seeding of bone marrow with haematopoietic progenitors and HSCs.


Bone marrow formation arbitrarily marks the end of the human embryonic period CS 23; 56 dpc O'Rahilly and Muller, 1987. In the mouse, this issue regulation of human haematopoietic stem cell self renewal addressed by pre-culturing embryonic tissues as explants to allow their further development ex vivo before assessing their haematopoietic potential Cumano et al. This approach was adopted for human studies and revealed that the human yolk sac and para-aortic splanchnopleura P-Sp; the precursor of the AGM region isolated prior to the onset of circulation at CS 10 21 dpc; to exclude cross-seeding possess differing haematopoietic potentials Tavian et al.

The yolk sac could generate only myeloid and natural killer NK cells, whereas the P-Sp showed a broader spectrum of haematopoietic differentiation including lymphoid B- and T-cell lineages starting from CS 11 24 dpcsuggesting that it could give rise to multipotent haematopoietic progenitors in vivo Tavian et al.

A subsequent study revealed that only the dorsal aorta and not the yolk sac contained so-called long-term cobblestone area-forming cells, which in bone marrow correlate with the presence of HSCs Oberlin et al.

Although these results are consistent with analyses in the mouse embryo, the human lympho-myeloid precursors revealed in culture may not be equal to true HSCs. Identification of the very few HSCs in the early human embryo required development of a robust in vivo long-term repopulation assay, which became possible only with the later advent of highly receptive xenograft mouse models.

The endothelial origin of human haematopoiesis Various non-human experimental models have shown that during development haematopoietic cells emerge from the embryonic endothelium Jaffredo et al.

Indeed, the endothelial-to-haematopoietic transition EHT is a multistep maturation process, which includes cell intermediates fully committed to the haematopoietic fate Taoudi et al. Importantly, although these cell intermediates express perhaps the most specific endothelial marker, VE-cadherin cadherin 5they are devoid of endothelial activity and are fully committed to the haematopoietic fate.

All haematopoietic tissues known from mouse studies, such as the AGM region, yolk sac, liver, umbilical cord and placenta Fig. Short tandem repeat analysis allowed for the discrimination between embryonic and maternal cells, which might contaminate samples, especially in placenta transplants.

In general, repopulation with yolk sac cells was significantly rarer than with AGM region cells. A robust presence of HSCs in the liver is generally detected later, from week 7-8 and the most potent subset of liver HSCs still express VE-cadherin, reflecting their endothelial origin Oberlin et al. At about the same time, severe combined immunodeficiency SCID mice, which could accept human haematopoietic grafts, were generated McCune et al.

These two factors largely defined progress in functional analysis of human HSCs.

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However, owing to residual NK cell activity, haematopoietic engraftment of human HSCs is attenuated, which especially affected experiments with low HSC numbers. This, together with the short lifespan of these mice, diminishes the utility of the model.

Whereas in the mouse HSCs develop in umbilical cord and placenta prior to liver colonisation de Bruijn et al. Only from week 9 of development are HSCs reliably detected in the human placenta Robin et al.

The aforementioned studies emphasise the importance of functional in vivo assays for the analysis of HSCs. Although immunohistological and in vitro studies suggested the appearance of HSCs in the CS 13 27-29 dpc liver Tavian et al.


The exceptional regenerative potential of the first human HSCs Transplantation of AGM cells after CS 14 30-32 dpc into immunodeficient mice results in long-term multilineage haematopoietic engraftment, confirming the presence of definitive HSCs Ivanovs et al.

As in the mouse, very few — normally only one — HSCs emerge in the human AGM region, as transplantation of cells from one human AGM into several recipients usually results in one haematopoietically reconstituted mouse Fig.

For comparison, this significant production of functional daughter HSCs exceeds the number required to prevent bone marrow failure in patients after myeloablation Catlin et al. Computational analysis of the repopulation dynamics suggested that adult human HSCs replicate every 40 weeks Catlin et al.

However, amplification of human AGM-derived HSCs from 1 to 300 in the recipient mouse over 6 months requires replication at least every 2-4 weeks, because transplanted HSCs also generate differentiated blood cells. The proliferation of the first HSCs in situ in the embryo may be even higher, given massive expansion of HSCs in the foetal liver.

The Hematologist