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Developmental Biology: Birth of the blood cell

Authors:
Momoko Yoshimoto at WMU Homer Stryker MD school of Medicine
Momoko Yoshimoto
  • WMU Homer Stryker MD school of Medicine
Mervin C Yoder at Indiana University – Purdue University Indianapolis
Mervin C Yoder
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Could it be that mouse fetal liver cells and adult bone-marrow blood cells originate from a subset of cells that line the blood vessels in the embryo? Several lines of evidence suggest that this is indeed the case.
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Developmental Biology: Birth of the blood cell
Momoko Yoshimoto and Mervin C. Yoder
Herman B Wells Center for Pediatrics Research, Indiana University, Indianapolis, Indiana 46202,
USA
Momoko Yoshimoto: ; Mervin C. Yoder: myoder@iupui.edu
Abstract
Could it be that fetal liver cells and adult bone-marrow cells originate from a subset of endothelial
cells that line blood vessels in the mouse embryo? Several lines of evidence suggest that this might
be the case.
During development, haematopoietic stem cells, which give rise to blood cells, and endothelial
cells, which line blood vessels, both form from the mesodermal germ-cell layer; exactly how
though is debatable. On one hand, a controversial, century-old theory proposes that both
haematopoietic and endothelial cells arise from a mesoderm-derived common precursor called
haemangioblast. On the other hand, a competing, relatively younger theory proposes that
haematopoietic stem cells form from a subset of early endothelial cells known as haemogenic
endothelium. The relationship between the haemangioblasts and haemogenic endothelium has
never been resolved. In this issue, however, three papers1–3 clarify the potential relatedness
and significance of these cell types.
The concept of haemangioblast initially arose from observations that, in the chick yolk sac,
haematopoietic stem cells (HSCs) and endothelial cells form aggregates called blood islands.
That blood-island formation in the mouse yolk sac is not a random process and requires
expression of specific genes such as Flk-1 provided further support for this concept. But the
strongest evidence for the existence of haemangioblasts came following the development of
an in vitro assay called blast colony-forming cell (BL-CFC) assay for analysis of differentiating
mouse embryonic stem (ES) cells4.
BL-CFC describes a population of single-celled (clonal) precursors that gives rise to cell
colonies with both HSC and endothelial features. When ES-cell-derived Flk-1-expressing
(Flk-1+) mouse cells are grown in culture, characteristic colonies appear, which consist of an
aggregate of non-adherent HSCs overlying an adherent layer of endothelium. This observation,
together with insights into the molecular regulation of blast-colony development and
differentiation4,5 have been enlightening. Nonetheless little has become clear of the cellular
events that herald the generation of the HSCs from BL-CFCs.
Lancrin et al.1 used time-lapse photography to analyse the sequence of cellular events required
for the formation of mature blast colonies from cultured Flk-1+ cells. They find that blast-
colonies form in two stages. First — after 36–48 hours of ‘plating’ Flk-1+ cells for growth in
culture — the cells form tightly adherent clusters. Subsequently, round non-adherent cells
appear, which then proliferate into mature blast colonies. Among the adherent-cell clusters at
48 hours, a transient cell population expressing various endothelial (but not mesodermal or
BL-CFC) markers appear, displaying the potential to form HSCs. From this cell population
eventually forms both primitive and definitive blood-cell colonies (characterized based on their
ability to express the protein haemoglobin).
NIH Public Access
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Nature. Author manuscript; available in PMC 2010 February 12.
Published in final edited form as:
Nature. 2009 February 12; 457(7231): 801–803. doi:10.1038/457801a.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Lancrin and colleagues' observations suggest that HSCs arise from haemangioblasts through
a haemogenic endothelial intermediate — the first linear pathway resolving, at least in vitro,
the relationship between haemangioblasts and haemogenic endothelium. But, do these finding
alter the definition of the haemangioblast? To answer this question, more must be learned about
the fate of the haemogenic endothelial cells following the birth of the HSCs. Equally, it will
be interesting to assess whether haemogenic endothelial cells differ from the cells producing
primitive and others definitive blood cells.
In numerous species, HSCs appear as clusters attached to the endothelium lining the ventral
wall of the aorta during embryonic development; this observation has long implicated the
endothelium to be the source of developing blood cells. Indeed, when endothelial cells obtained
from mouse embryos are grown in culture, a subset of them display the potential to develop
into mature blood cells such as erythroid, myeloid and/or lymphoid cells6. But despite this and
other indirect evidence7, direct proof of HSCs emerging from individual endothelial cells has
been lacking.
Eilken et al.2 (page YYY) tracked the fates of all cells (over 6500) generated from individually
plated mouse ES-cell-derived mesoderm cells using time-lapse microscopy. Their detailed
analysis of the resulting colonies indicates that 1.2% of the colonies display properties of
adherent endothelial cells, and that one or more endothelial cells in a colony directly give rise
to non-adherent HSCs. The authors also directly isolated primary endothelial cells with
haemogenic potential from early mouse embryos. They therefore demonstrate that haemogenic
endothelial cells are present in mouse embryos and can be generated in vitro from ES cells
during a narrow window of development. But the question that these authors2 and Lancrin et
al.1 did not address is whether HSCs emerge directly from haemogenic endothelial cells in
vivo during mouse development.
In the developing mouse embryo, the transcription factor Runx1 is required for the formation
of HSCs and their progenitors. In fact, Runx1 has been considered necessary for the emergence
of HSC clusters from the haemogenic endothelium8. Chen et al.3 (page 000) show that, within
the endothelium, Runx1 expression is indeed essential for the formation of HSCs and their
progenitors over a period of roughly 3 days during mouse embryonic development (embryonic
day 8.25–11.5). Furthermore, in agreement with another recent report9, they show that most
fetal liver cells and adult bone-marrow cells are born from the endothelium. So embryonic
haemogenic endothelial cells seem to be the source of Runx1-dependent HSCs and their
progenitors that populate the fetal liver and the adult bone marrow.
Together, these studies1–3 provide substantial evidence that HSCs and progenitor cells of the
blood lineage are born of the differentiated endothelium forming functional vasculature in the
mouse conceptus. The focus therefore can now turn on determining the intriguing molecular
mechanisms involved, which might differ between the various embryonic sites of blood-cell
production10. What's more, translation of this knowledge to humans could be of great assistance
in generating human HSCs from human ES cells, either by direct cell reprogramming11 or
indirectly through induced pluripotent stem cells.
References
1. Lancrin C, et al. Nature 2009;457:892–895. [PubMed: 19182774]
2. Eilken HM, Nishikawa SI, Schroeder T. Nature 2009;457:896–900. [PubMed: 19212410]
3. Chen MJ, Yokomizo T, Zeigler BM, Dzierzak E, Speck NA. Nature 2009;457:887–891. [PubMed:
19129762]
4. Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. Development 1998;125:725–732.
[PubMed: 9435292]
Yoshimoto and Yoder Page 2
Nature. Author manuscript; available in PMC 2010 February 12.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
5. Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G. Nature 2004;432:625–630. [PubMed: 15577911]
6. Nishikawa SI, et al. Immunity 1998;8:761–769. [PubMed: 9655490]
7. de Bruijn MF, et al. Immunity 2002;16:673–683. [PubMed: 12049719]
8. Yokomizo T, et al. Genes Cells 2001;6:13–23. [PubMed: 11168593]
9. Zovein AC, et al. Cell Stem Cell 2008;3:625–636. [PubMed: 19041779]
10. Dzierzak E, Speck NA. Nature Immunol 2008;9:129–136. [PubMed: 18204427]
11. Gurdon JB, Melton DA. Science 2008;322:1811–1815. [PubMed: 19095934]
Yoshimoto and Yoder Page 3
Nature. Author manuscript; available in PMC 2010 February 12.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Figure 1.
Relationship between endothelial cells and blood cells. Endothelial cells line the inside of blood
vessels. During mouse embryonic development, a subset of these cells, known as haemogenic
endothelial cells, seems to give rise to haematopoietic stem cells (HSCs) and their progenitors,
such as those that seed the fetal liver and the adult bone marrow.1–3
Yoshimoto and Yoder Page 4
Nature. Author manuscript; available in PMC 2010 February 12.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
... Anatomical sites in which HSCs proliferate and differentiate are known to change sequentially during fetal ontogenesis [1,2]. In mouse and human, HSCs emerge in the endothelial layer of developing arteries prior to midgestation, in response to blood flow caused by cardiovascular contraction [3][4][5][6]. Then, HSCs migrate to the liver and spleen, and thereafter to the bone marrow, which is the main HSCs migrate to the liver and spleen, and thereafter to the bone marrow, which is the main hematopoietic organ. ...
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