Cell Signaling During Primitive Hematopoiesis
lineage progenitors. In species in which
such assays are possible, HSCs are not
detected prior to the emergence of prim-
itive progenitors. It is presently unclear,
however, whether the inability to detect
primitive HSCs is because of experimen-
tal limitations or because they simply do
not exist.
In addition to primitive erythroid and
primitive myeloid progenitors, primitive
hematopoietic tissue has also been demon-
strated to give rise to deFnitive progen-
itors and possibly some deFnitive HSCs
in a species-speciFc manner. The rela-
tionship between primitive hematopoiesis
ing vertebrate embryo, particularly in
the mouse, is somewhat contentious. Of
some controversy is whether HSCs with
deFnitive potential produced in primitive
hematopoietic sites contribute to deFni-
tive hematopoiesis
in vivo
or if HSCs
with deFnitive potential are produced
de novo
in the embryo, at sites where
cur. Historically, researchers believed that
the yolk sac gives rise to HSCs that
subsequently seed the embryonic sites
of deFnitive hematopoiesis, the aorta-
gonads-mesonephros region and liver, and
thus give rise to all deFnitive lineages. This
belief was supported by the observation
that hematopoietic cells emerge Frst in the
yolk sac and then later in the liver during
embryogenesis. Moreover, it was shown
that cultured embryos lacking yolk sacs
fail to carry out deFnitive hematopoiesis.
Two subsequent experimental approaches
seriously challenged this conclusion. ±irst,
it was shown that transplanting quail
embryos onto stage-matched precircula-
tory yolk sacs (Hamburger-Hamilton [HH]
stage 9) from chick embryos and allowing
them to develop
in vivo
resulted in quail fe-
tuses in which all deFnitive hematopoietic
cells were derived from the quail em-
bryo. The results from this experiment
incontrovertibly ruled out any yolk sac con-
tribution to deFnitive hematopoiesis after
HH stage 9 in the chick. Strikingly, in
the mouse, HSCs are detected after E10
three days after primitive erythroid cells
are Frst detected), Frst in the aorta-gonads-
mesonephros region and subsequently in
the yolk sac. ±urthermore, fragments of
mouse embryo including aorta-gonads-
mesonephros mesodermal precursors, iso-
lated from precirculatory embryos, can
fully reconstitute a genetically deFcient
adult host if the precursor-containing frag-
ment is maintained in culture prior to
transplantation. Together, these data sug-
gest that the aorta-gonads-mesonephros
region is the source of deFnitive HSCs,
and not the yolk sac. Moreover, it has been
suggested that some of these aorta-gonads-
mesonephros-derived HSCs enter the yolk
sac via the circulation, thus explaining the
presence of HSCs with deFnitive poten-
tial found later in the yolk sacs of chick
and mouse around the time that primitive
hematopoiesis diminishes.
Although these and other experiments
have led many to conclude that the yolk
sac is not a source of deFnitive HSCs,
these data do not completely rule out
that there is a primitive contribution to
deFnitive HSCs in the fetus. The failure
to detect yolk sac HSCs in mouse em-
bryos before E11 might be explained if
HSCs are present at this time, but are
not yet competent to respond or home
to the adult hematopoietic microenviron-
ment when they are transplanted into adult
hosts. ±or example, deFnitive HSCs can
be detected in E9 – 10 yolk sacs when the
yolk sac cells are transplanted into chemi-
cally myeloablated livers of newborn hosts.
Grafted yolk sac cells are capable of sup-
porting hematopoiesis in the recipients for
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