Cell Signaling During Primitive Hematopoiesis
nearly a year after transplant. Detection of
HSCs from E8 precirculatory murine yolk
sacs after a period of coculture with a
stromal cell line has also been observed,
lending further support to the idea that
deFnitive HSCs are produced in the same
location and during the same period of
embryogenesis as are primitive progeni-
tors. Interestingly, mouse embryonic stem
cells (pluripotent embryo-derived stem
cells that are believed to faithfully recapitu-
late primitive and deFnitive hematopoiesis
in vitro
) cultured under conditions that
promote hematopoietic speciFcation and
differentiation, give rise to clonal colonies
(i.e. colonies derived from a single cell) that
contain both primitive erythrocytes and
deFnitive hematopoietic cells. These data
lend some credence to the idea that prim-
itive and deFnitive hematopoietic cells
point to the need for better methods to
detect HSCs in embryos. In particular,
identifying groups of genes that are ex-
pressed and function speciFcally in HSCs
would tremendously aid in HSC detection.
A second possible explanation for the
failure to detect yolk sac-derived HSCs is
that assays that have been used to assess
the origins of HSCs, such as culturing
fragments of precirculatory embryos, do
not address the possibility that HSCs may
be generated in the early yolk sacs of chicks
and mice and then migrate interstitially
into the embryo prior to the onset of
circulation. Interestingly, at the same
time that morphological and molecular
evidence of hematopoietic development
is observed in mouse embryos (E7–7.5),
primordial germ cells are also formed
in the yolk sac. These primordial germ
cells migrate into the embryo before
circulation begins, reaching the gonads
(in the aorta-gonads-mesonephros region)
later in development. Perhaps an early
population of HSCs migrates into the
embryos with the primordial germ cells. To
adequately address the issue of whether the
murine yolk sac contributes to functional,
deFnitive HSCs, a reliable method for
performing stage-speciFc
in vivo
analysis of mouse yolk sac derivatives
is required. Unfortunately, this will not
be a trivial task given the difFculty of
in utero
transplantation, the inability to
culture whole mouse embryos past E10.5
and the current lack of molecular tools
to direct expression of heritable lineage
markers in putative yolk sac HSCs. Until
suitable technologies that allow for directly
testing the fate of yolk sac hematopoietic
cells are created, this issue will likely
remain unresolved.
Whereas the presence of deFnitive HSCs
during primitive hematopoiesis is still
debated, it is well accepted that some
deFnitive progenitors are generated in
the primitive hematopoietic site, also in a
species-speciFc manner. ±or example, iso-
lated yolk sac cells from mouse embryos
can give rise to deFnitive erythrocytes
and other deFnitive hematopoietic cell
types under appropriate culture condi-
tions. The kinetics with which these com-
mitted hematopoietic progenitors emerge
in the mouse yolk sac, and subsequently
in the aorta-gonads-mesonephros and liver
suggest that progenitors generated in
the yolk sac enter circulation, seed the
fetal deFnitive hematopoietic sites and
contribute differentiated deFnitive blood
cells during fetal development. Similarly
, detailed fate mapping of
the ventral blood islands revealed that
it contributes not only to primitive ery-
throcytes, but also to a small but sig-
niFcant number of thymocytes (T-cells)
and B-cells in premetamorphic animals.
A small contribution of ventral blood is-
land cells to deFnitive erythrocytes and
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