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First published online September 12, 2006
doi: 10.1242/10.1242/dev.02568

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The journey of developing hematopoietic stem cells

¹ Department of Molecular, Cell and Developmental Biology, Jonsson Comprehensive Cancer Center, Institute for Stem Cell Biology and Medicine, University of California, Los Angeles, CA 90095, USA.
² Department of Pediatric Oncology, Dana-Farber Cancer Institute/Children's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Howard Hughes Medical Institute, Boston, MA 02115, USA.

View larger version (27K): [in a new window]   Fig. 1. Hematopoietic organs in mouse and human embryos. An illustration of (A) a mouse and (B) a human embryo, showing the hematopoietic organs at 11 days and 5 weeks of gestation, respectively (yellow, yolk sac; green, dorsal aorta; red, fetal liver; blue, umbilical vessels and fetal vasculature in the placenta). The hematopoietic function of the human placenta has not yet been experimentally proven. AGM, aorta-gonad-mesonephros region.

View larger version (20K): [in a new window]   Fig. 2. Establishment of definitive hematopoietic stem cell (HSC) pools in mouse and human embryos. (A) Hematopoietic development starts as specification of primitive streak mesoderm (gray) into hematopoietic and vascular fates. Nascent HSCs undergo a maturation process (blue) that allows them to engraft, survive and self-renew in future hematopoietic niches. Subsequently, fetal HSCs expand rapidly, after which a steady state is established in which HSCs reside in a relatively quiescent state in the bone marrow. (B) The ages at which mouse and human hematopoietic sites are active. Gray bars, mesoderm; red bars, active hematopoietic differentiation; yellow bars, HSC genesis; blue bars, presence of functional adult-type HSCs. Broken yellow bars for yolk sac and placenta indicate that de novo HSC genesis has not been experimentally proven.

View larger version (18K): [in a new window]   Fig. 3. Assays for fetal hematopoietic stem cell (HSC) development. (A) (Top panel) An E10.5-11 mouse embryo. HSCs can be reliably assayed only by transplanting them into myeloablated (e.g. irradiated) recipients (lower panel) and then documenting their ability to give rise to sustained (3-6 months) multilineage hematopoietic reconstitution. Functional adult-type HSCs that can achieve such reconstitution in this assay are found only in mouse embryos or extra-embryonic tissues after E10.5-11.5. (B) (Top panel) A mouse embryo at E9.0. HSC activity can be observed at a younger age, and higher hematopoietic chimerism from immature HSCs (pre-HSCs) can be obtained if more permissive recipients (e.g. newborn mice, Rag2-/- c-/- mice, lower left) are used. Transplantation directly into the long bones of a recipient can also improve engraftment (lower right). Intermediate explant culture of pSP cells also allows detection of HSC activity at a younger age.

View larger version (78K): [in a new window]   Fig. 4. Localization of developing hematopoietic stem cells (HSC)s in the mouse embryo. Immunohistochemistry of E10 Runx1-lacZ mouse embryo shows Runx1-lacZ-expressing cells (blue) are present in (A) the dorsal aorta and the adjacent mesenchyme (ventral, top left-hand corner), and (B) the yolk sac. Although not all Runx1-positive cells are HSCs, all developing HSCs and progenitors express Runx1 and are therefore postulated to reside within the Runx1-expressing cell population. Runx1-lacZ, blue; laminin, red. Arrows indicate Runx1-lacZ-expressing cells. Images provided by H.K.A.M.

View larger version (14K): [in a new window]   Fig. 5. Migratory and circulatory routes that connect fetal hematopoietic sites. The primitive streak (gray) gives rise to the hemogenic mesoderm/hemangioblasts that migrate into the yolk sac (yellow), paraaortic splanchnopleurae (pSP)/aorta-gonadmesonephros (AGM) region (green) and possibly through the allantois to the placenta (blue). Hematopoietic specification most probably occurs during the migratory process. The two main circulatory routes that connect fetal hematopoietic organs during midgestation are vitelline and umbilical circuits. The vitelline artery connects the upper dorsal aorta to the yolk sac, which connects to the fetal liver (red) via the vitelline vein. The umbilical artery connects the caudal part of dorsal aorta to the placenta, which connects to the liver via the umbilical vein. Although budding into the lumen and seeding through circulation has been hypothesized as the main route by which nascent HSCs seed the fetal liver, direct migration of hematopoietic stem cells (HSCs) from the AGM to the fetal liver has not been formally excluded (indicated by `?'). Broken arrows indicate the migration of HSC precursors and unbroken arrows indicate circulation of HSCs through vasculature. Bone marrow (orange) is seeded by HSCs before birth. Larger black arrows indicate major HSC trafficking. The timing of these events is outlined by the timescale in embryonic days below.