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First published online June 20, 2008
doi: 10.1242/10.1242/dev.021279
Jeem Classic |
1 Erasmus MC, Erasmus Stem Cell Institute, Department of Cell Biology, PO Box
2040, 3000 CA Rotterdam, The Netherlands.
2 University of Edinburgh, MRC Centre for Regenerative Medicine/Institute for
Stem Cell Research, Kings Buildings, West Mains Road, Edinburgh EH9 3JQ,
UK.
e-mails: e.dzierzak{at}erasmusmc.nl; a.medvinsky{at}ed.ac.uk
SUMMARY
This essay is about the 1975 JEEM paper by Françoise
Dieterlen-Lièvre
(Dieterlen-Lièvre,
1975
) and the studies that followed it, which indicated that the
adult hematopoietic system in the avian embryo originates, not from the blood
islands of the extraembryonic yolk sac as was then believed, but from the body
of the embryo itself.
Dieterlen-Lièvre's 1975
paper created a paradigm shift in hematopoietic research, and provided a new
and lasting focus on hematopoietic activity within the embryo body.
Introduction
Until the mid-1970s, developmental studies of the blood focused on the
extraembryonic tissue, the yolk sac, as being the source of the adult
hematopoietic system. In 1965, it was demonstrated, using twin and parabiosed
(joined by their circulation) chick embryos, that circulating blood cells
colonized the spleen and bone marrow during development
(Moore and Owen, 1965). Later,
in 1967, it was shown that transplanted yolk sac cells could populate the
spleen and bone marrow of later-stage, irradiated, avian embryos
(Moore and Owen, 1967). It is
not difficult to imagine why the yolk sac was the focus of attention and
thought to be the source of adult hematopoiesis. The fact that the yolk sac is
the earliest tissue in the embryo that shows hematopoietic activity during
development has been known to embryologists for a long time, and has,
therefore, attracted particular scrutiny. As long ago as the early 1900s,
Sabin described the morphological similarity that is evident between emerging
blood cells and vascular cells in the chick yolk sac blood islands
(Sabin, 1920). This gave rise
to the concept of the hemangioblast
(Murray, 1932), the common
mesodermal precursor of the hematopoietic and endothelial lineages.
During the 1970s, the relevance of these findings to mammalian species was
investigated in mouse models (reviewed by
Dzierzak and Speck, 2008).
Aided by in vitro and in vivo assays to identify hematopoietic progenitors and
hematopoietic stem cells (HSCs), Moore and Metcalf performed a detailed
investigation of the temporal and spatial appearance of hematopoietic cells in
the mouse conceptus (Moore and Metcalf,
1970). For the first time, immature progenitors that form large
hematopoietic colonies in the spleen (colony forming units-spleen, CFU-S), and
cells that repopulate the hematopoietic system of adult irradiated recipients
(HSCs), were detected in the yolk sac. Both cell types, CFU-S and HSCs, are
associated with adult hematopoiesis. Additional experiments showed that the
appearance of hematopoietic activity in explants of the body of the embryo
depended on the presence of the yolk sac. Based on these, and other reports
(Weissman et al., 1977), it
was accepted that the mammalian adult hematopoietic system, as was suggested
in the chick at that time, originated in the yolk sac, and that these cells
migrate to and colonize the adult blood tissues. It was in this scientific
context and atmosphere that the developmental studies by
Dieterlen-Lièvre came into play.
The 1975 JEEM publication by Dieterlen-Lièvre on the
intraembryonic origins of the avian adult hematopoietic system is a true
classic (Dieterlen-Lièvre,
1975). The results of her chick-quail embryo grafting experiments
initiated an important paradigm shift in the field. Her results demonstrated
that, in the avian species, it is the embryo body, not the yolk sac, that is
the true source of cells for the adult blood system. Yolk sac-derived cells
exist only transiently and do not contribute to the adult blood system. Later
findings in amphibian embryo grafting and cell-tracing experiments supported
an independent, intraembryonic source of adult hematopoietic cells
(Ciau-Uitz et al., 2000;
Kau and Turpen, 1983;
Maeno et al., 1985;
Turpen et al., 1981). However,
the intraembryonic origin of adult hematopoiesis continued to be a hotly
debated topic. At the heart of the controversy was whether findings in
non-mammalian vertebrate embryos could accurately reflect the developmental
origins of the adult hematopoietic system in mammalian embryos.
It took almost 20 years before Dieterlen-Lièvre's findings were
fully appreciated for their widespread impact on studies concerning the
developmental origins of adult hematopoiesis in a variety of metazoans,
including mammals. Her elegant yolk sac chimera experiments and novel
discoveries, as discussed in more detail below, inspired a new wave of
investigation into the temporal and spatial origins of the adult hematopoietic
system, particularly in the mammalian conceptus. On a personal note, her work
had a profound impact on us and on others in the early 1990s, as we searched
for and found regions of potent intraembryonic hematopoietic activity in mouse
midgestation embryos (Godin et al.,
1993; Medvinsky et al.,
1993). Although an increasing amount of molecular data supported
the idea that blood developmental mechanisms were conserved among various
animal models, it was the reading of Dieterlen-Lièvre's pioneering work
in JEEM that inspired the careful re-examination of mouse
hematopoietic development and that paved the way to developmental
hematopoietic studies in other vertebrates, including in humans, frogs and
zebrafish.
Yolk sac chimeras: the approach taken by Dieterlen-Lièvre
Unequivocal proof that the hematopoietic cells of the adult avian originate
in the body of the embryo came from a new experimental approach in which a
whole embryo body of one avian species was grafted onto the yolk sac of
another species (Dieterlen-Lièvre,
1975; Martin,
1972).
In contrast to the intrauterine development of mammalian embryos, avian
embryos are easily accessed and are amenable to manipulations in which cells,
tissue rudiments or territories are exchanged between species to follow cell
morphogenesis, migration and organogenesis during development
(Le Douarin, 1973;
LeDouarin and Jotereau, 1973).
The flatness of the avian embryo as it lies on the surface of the spherical
yolk sac facilitates its dissection, allowing it to be replaced with the
embryo of another species in ovo. When such manipulations were carried out, it
was noted that there was a rapid reconstitution and joining of blood vessels
between the grafted embryo body and the host yolk sac, and that the free
circulation of blood cells was established between the yolk sac and the body,
without any disruptions to normal development in the resulting chimeras
(Martin, 1972).
|
). Additional experiments verified that chick cells were
capable of colonizing quail spleen rudiments in intracoelomic grafts. Thus,
the interspecific avian chimeras proved that the body of the avian embryo
generates the hematopoietic cells that seed the adult tissues.
This conclusion was later confirmed and advanced in studies that used
homo-specific yolk sac chimeras generated from chick embryos of different
sexes or from congenic chick strains that differed in histocompatibility
markers (Beaupain et al., 1979;
Lassila et al., 1978;
Lassila et al., 1982;
Martin et al., 1978). The
combined results and conclusions of many such yolk sac chimera experiments are
highlighted in Box 1.
| Box 1. A summary of findings from avian yolk sac chimera
experiments
|
These results were in striking contrast to the generally held dogma of the yolk sac origins of hematopoiesis in mammals (Fig. 2A), and suggested at least two waves of hematopoietic cell generation (Fig. 2B): a first wave that consists of primitive transitory, short-lived blood cells from the yolk sac; and a second wave that originates from the embryo body and that generates the permanent, long-lived adult hematopoietic system.
Other pivotal studies in avian developmental hematopoiesis
The findings of these avian chimera studies prompted
Dieterlen-Lièvre to search for the source of hematopoietic cells in the
body, leading her laboratory to focus on the diffuse hematopoietic foci in the
dorsal aorta that had been described in vertebrate embryos decades earlier
(Emmel, 1916;
Jordan, 1916;
Miller, 1913), but which had
been neglected by the literature at that time. Her detailed anatomical
descriptions of the microscopic hematopoietic cell clusters that are present
on the ventral wall of the avian embryonic dorsal aorta
(Dieterlen-Lièvre and Martin,
1981) were followed by studies in mouse and human embryos
(Garcia-Porrero et al., 1995;
Tavian et al., 1996) (reviewed
by Jaffredo et al., 2005).
This aortic region was found to contain multipotential hematopoietic
progenitors at the time when hematopoietic cell clusters appear on its ventral
aspect (Cormier and
Dieterlen-Lièvre, 1988). The close association of
hematopoietic and endothelial cells led to the speculation that either
hemogenic endothelial cells exist on the ventral aspect of the aorta or that
hemangioblasts are present in foci in the underlying para-aortic mesenchyme
(Dieterlen-Lièvre and Martin,
1981).
To examine whether the hematopoietic cells in these clusters derive from
endothelial cells, embryonic aortic endothelial cells were labelled with the
lipophilic lipoprotein DiI-LDL, which was injected into the chick heart cavity
during pre-hematopoietic embryonic stages
(Jaffredo et al., 1998) to
allow its uptake by the aortic endothelium. One day later, DiI-LDL-labelled
intra-aortic hematopoietic clusters on the ventral aspect of the aorta were
found, suggesting that they originated from the endothelium. The ability of
endothelial cells to give rise to hematopoietic cells was also supported by
culture experiments (Nishikawa et al.,
1998).
The inclusion of the allantoic bud in the quail bodies that were grafted in
the 1975 experiments
(Dieterlen-Lièvre,
1975) raised the possibility that it might also give rise to
hematopoietic cells. Indeed, later grafting experiments undertaken by
Dieterlen-Lièvre identified another embryonic territory capable of
hematopoietic cell generation, the allantois
(Caprioli et al., 1998). The
prevascularized quail allantoic bud was grafted into the coelom of a chick
host. Quail-derived cells of both the hematopoietic and endothelial lineages
were found in the bone marrow of the host, demonstrating that their precursors
arose in the allantois. Hence, both the allantois and the embryo proper can
contribute to the adult avian blood system.
From dogma to new sites of mammalian hematopoietic cell generation
Avian embryo in ovo grafting studies have greatly influenced developmental
hematopoiesis research in other animal models. In the absence of the ability
to grow mouse conceptuses ex utero for similar studies, short-term explant
cultures of individual mouse embryonic tissues, together with in vitro and in
vivo hematopoietic assays, have been used to investigate their hematopoietic
potential. Early studies with mouse yolk sac and with whole embryo body
explants (before the establishment of the circulation at E7-E8.5) have
suggested that the embryo body hematopoietic activity is acquired through
colonization from the yolk sac (Moore and
Metcalf, 1970). However, the discovery of enriched hematopoietic
activity within the avian embryonic dorsal aorta prompted a more precise
spatial and temporal re-evaluation of this region in the mouse embryo.
|
;
Medvinsky et al., 1993) and
HSCs capable of long-term multilineage reconstitution of adult irradiated
recipients (Muller et al.,
1994) were localized to this area. As shown in explant cultures,
the PAS (at the pre-circulation stage) produces the first multipotent
(lymphomyeloid) hematopoietic progenitors
(Cumano et al., 1996).
Importantly, at E10.5, the AGM region autonomously generates the first HSCs
that are as potent as those found in the adult
(Medvinsky and Dzierzak,
1996). The generation of these functionally complex hematopoietic
progenitors and adult-type HSCs by the PAS/AGM precedes the appearance of such
cells in the mouse yolk sac. HSCs localize to the aortic endothelium and to
hematopoietic clusters (de Bruijn et al.,
2002; North et al.,
1999; North et al.,
2002), and map to the ventral aspect of the dorsal aorta
(Taoudi and Medvinsky, 2007).
Similarly, the human PAS/AGM region autonomously generates potent
hematopoietic progenitors prior to their appearance in the yolk sac
(Tavian et al., 2001).
Hematopoietic cell clusters are also found on the ventral aspect of the human
aorta at this developmental time (Tavian
et al., 1996).
Recently, the mouse allantois has, as in avian embryos, also been found to
be a site of hematopoietic cell potential
(Corbel et al., 2007;
Zeigler et al., 2006).
Hematopoietic progenitors and HSCs are found in the vitelline/umbilical
arteries (de Bruijn et al.,
2000) and in the chorio-allantois placenta
(Alvarez-Silva et al., 2003;
Gekas et al., 2005;
Ottersbach and Dzierzak,
2005). Thus, hematopoiesis in the mouse conceptus closely
parallels that of avian embryos, and it is likely that mouse AGM HSCs and
their progeny provide (at least in part) the life-long adult hematopoietic
system.
Unanswered questions
The controversy that surrounds whether adult mammalian hematopoiesis
originates from the yolk sac persists to this day, despite a wealth of
molecular, cellular and functional data from various animal models that
indicate otherwise. Recent studies have shown that mouse embryos with
defective circulation (Lux et al.,
2008), or that are deficient for cell migration
(Ghiaur et al., 2008), develop
hematopoietic cells in the yolk sac but not in the embryo. Clearly, these
experiments indicate that the yolk sac generates hematopoietic progenitors
that may colonize the body of the embryo. However, the absence of
hematopoietic progenitors in the body may not be indicative of the absence of
HSCs. The midgestation lethality of these mutant embryos precluded direct HSC
analysis, but one may hope that alternative approaches
(Yoder et al., 1997) will shed
light on whether the precursors of HSCs develop in the yolk sac.
In this context, Dieterlen-Lièvre's avian embryo chimera
experiments, which suggested that permanently functioning adult HSCs could be
generated by the conceptus independently of a transient population of
hematopoietic progenitors, have changed the landscape of the field of
developmental hematopoiesis. Dieterlen-Lièvre's avian yolk sac chimera
data indicated that the body of the avian embryo is a `maternity ward' for the
generation of HSCs (Metcalf,
2008), making it very likely that the mouse AGM also plays this
role. However, the mouse AGM might also have an additional function as a
`finishing school' for yolk sac hematopoietic progenitors, influencing them to
become HSCs. Further insights into the role(s) of the mouse AGM (as well as
the yolk sac and placenta) await the development of new experimental
approaches and solutions.
In conclusion, avian embryos remain informative developmental models that have provided crucially important insights into mammalian development. The insights provided by Dieterlen-Lièvre's avian yolk sac chimera experiments initiated a paradigm shift that continues to inform and to challenge research in the field of developmental hematopoiesis to this day.
ACKNOWLEDGMENTS
We thank Thierry Jaffredo for his helpful comments on the text. Our work in this field is supported by the National Institutes of Health, Dutch BSIK Innovative and ZonMW VICI programs for E.D., and by the MRC and Leukaemia Research (UK) for A.M.
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