432
Cell Signaling During Primitive Hematopoiesis
after metamorphosis. ZebraFsh primitive
erythroblasts
are
produced
in a
syn-
chronous
wave
in
the
lateral
meso-
derm and are morphologically detectable
within the intermediate cell mass at
20 hours postfertilization (hpf). Subse-
quently, they enter embryonic circulation
around 24 hpf, where they complete matu-
ration around 5 days postfertilization (dpf).
Until 4 dpf, primitive erythrocytes are the
only red cells in the blood stream; deFni-
tive cells begin to circulate at 5 dpf.
Although primitive hematopoiesis is of-
ten deFned as the production of primitive
erythrocytes, primitive leukocytes are also
generated in some species. The exact
in vivo
function of primitive leukocytes
has not been well characterized, however.
In the mouse, megakaryocyte progenitors
are detectable in cultured E7.5 yolk sac
cells and primitive megakaryocytes are ev-
ident in the yolk sac of intact embryos
at E8.5. Primitive megakaryocytes differ
signiFcantly from their deFnitive counter-
parts by their smaller size, rapid differ-
entiation kinetics, chromosome number,
and response to cytokines
in vitro
.I
thas
been suggested that primitive megakar-
yocytes play a role in maintaining early
blood vessel integrity through production
of platelets, but this possibility remains
to be tested. It is not known whether
other vertebrates also produce primitive
megakaryocytes. Primitive macrophages
are found in all vertebrates and differ
signiFcantly from deFnitive macrophages
in many ways, including their phagocytic
activity. Electron microscopic studies of
the mouse embryo demonstrated the pres-
ence of macrophage cells in the yolk sac
at E7. Macrophage progenitors are de-
tected in early mouse embryos at the same
time and place that primitive erythroid
progenitors are Frst detected, suggest-
ing that the yolk sac is also a source of
macrophage progenitors. In
Xenopus
,the
ventral blood island gives rise to circulat-
ing macrophages but a larger, nonventral
blood island–derived macrophage popula-
tion originates from a region anterior to the
heart and migrates interstitially through-
out the mesenchyme of the larval body.
Recently, it was demonstrated that in ze-
braFsh, a similar population of migrating
macrophages develop from a site anterior
to the primitive erythroid site. Presum-
ably, macrophages that develop during
primitive hematopoiesis function to re-
move dead cells from the embryo and are
involved in tissue remodeling. In sum-
mary, although primitive hematopoiesis
mostly contributes primitive erythrocytes,
it also yields a number of non-erythroid
myeloid cells. ±urther characterization of
these primitive myeloid populations will
reveal their functions in the early embryo.
Although multiple primitive blood lin-
eages are detected in some vertebrate
species, there is no experimental evidence
demonstrating that primitive blood cells
are derived from HSCs. Markers that
uniquely identify HSCs are currently not
known; therefore, HSCs are experimen-
tally deFned as self-renewing cells that
can provide long-term hematopoietic re-
constitution of an adult host. SpeciFcally,
embryonic HSCs are detected by dissoci-
ating embryos or embryo fragments into
single cells and transplanting these cells
into adults that typically lack their own
functional hematopoietic system because
they have been irradiated or they carry
genetic mutations that impair normal
hematopoiesis. If the transplanted embry-
onic cells contain HSCs, and these HSCs
can home to and engraft sites that support
hematopoiesis, blood lineages are recon-
stituted and long-term survival is achieved
because the embryo-derived HSCs can
self-renew and continuously supply blood
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