Embryogenesis Of Hematopoietic And Lymphopoietic Organs

Establishment of hematolymphopoietic organs in the mouse initiates with the formation of pluripotential hemolymphopoietic stem cells (HSC) in intraembryonic splanchnopleura and is followed by a temporal migration of these HSC from intraembryonic mesenchyme in this region to the fetal liver, fetal spleen, and ultimately to final residence in bone marrow and in the thymus (Metcalf and Moore 1971; Diet-erlen-Lievre 1975; Good 1995; Medvinsky and Dzierzak 1996). HSC are a unique

T Cell

B Cell

Erythrocyte

Platelets

Monocyte

Eosinophil Basophil

Basophil progenitor

Figure 1.1 Overview of the hematopoietic system detailing lineage relationships between hematopoietic stem cells (HSC) and lineage-restricted stem cells for hematopoietic and immunocompetent cells.

T Cell

B Cell

Erythrocyte

Platelets

Monocyte

Granulocyte-monocyte (Q ) Neutrophil progenitor

Eosinophil Basophil

Basophil progenitor

Figure 1.1 Overview of the hematopoietic system detailing lineage relationships between hematopoietic stem cells (HSC) and lineage-restricted stem cells for hematopoietic and immunocompetent cells.

population of cells that maintain the capacity to self-renew to repopulate themselves when the system is depleted, proliferate to expand the numbers of cells that become committed to development down a specific blood cell lineage, and differentiate to form all of the morphologically identifiable leukocytes that participate in immune responses, as well as megakaryocytic and erythrocytic cells (Terskikh et al. 2003; Weissman 2000) (Figure 1.1).

HSC first appear in mice during the 8th gestational day in intraembryonic splanch-nopleuric mesenchyme surrounding the heart (Cumano and Godin 2001), a tissue also identified as the aorto-gonado-mesonephros (AGM) (Figure 1.2). HSC are found at essentially the same embryonic stage in extraembryonic blood islands of the yolk sac in rodents as well (Marcos et al. 1997). It remains unclear to what extent there is an exchange of cells from intraembryonic hematopoietic tissues to these extraem-bryonic tissues and whether this exchange is responsible for the appearance of HSC in those anatomic sites. Circulation in the embryo is not established until gestational day 8 in embryonic mice, making this exchange likely; however, it is also clear that HSC in these two tissues differ dramatically in developmental fate (McGrath et al. 2003). Recent studies have clearly shown that intraembryonic stem cells, but not those which appear in the yolk sac, ultimately contribute to sustained intraembryonic blood cell development in the embryo and to the emergence of functional immune responsive cells in rodents (Godin et al. 1999; Cumano et al. 2001). One interpretation of these results is that HSC in extraembryonic sites derive separately and have severely restricted developmental potential as compared to those that arise in intraembryonic tissues. It should be noted that both of these populations of HSC form spleen colonies (day 12 CFU-s) following in vivo transplantation of AGM or

Birth

Yolk Sac

Splanchnopleura AGM Region

Thymus

Fetal Liver

Spleen

Bone Marrow

11.5 13.5 15.5 17.5 Days of Gestation

Figure 1.2 Ontogeny of hematopoiesis in rodents.

yolk sac cells in rodents a standard assay for pluripotential hematopoietic cells (Till and McCulloch 1961; Magli et al. 1982).

This initial period of de novo development of hematolymphoid stem cells from uncommitted mesenchymal cells culminates as these cells migrate to other intraem-bryonic anatomic locations in the fetus, primarily the liver and spleen (Metcalf and Moore 1971; Tavassoli and Yoffey 1983). In these new tissues, lineage-restricted subpopulations of stem cells begin to emerge and expand. This second wave of hematolymphoid development, characterized by emergence of committed stem cells for lymphoid and myeloid cell production, initiates in the liver on gestational day 10 in mice (Godin et al. 1999).

At approximately day 10 of gestation in mice, HSC relocate from the AGM to the developing fetal liver organ (Tavassoli 1991; Delassus and Cumano 1996; Godin et al. 1999; Cumano and Godin 2001). As HSC accumulate in the fetal liver, these cells differentiate to form the complex array of progressively more differentiated and lineage-restricted stem cells that characterize postnatal hematopoietic tissues (Mebius et al., 2001). This appearance and expansion of lineage-restricted stem cells is followed by differentiation of the same cells to form more mature progenitor cells that retain the ability to proliferate. These committed cells do not self-renew and are further restricted in their developmental options. Lineage-restricted cells are operationally defined by their proliferation and differentiation in response to a known set of colony stimulating factors (CSFs) and the formation of characteristic colonies in vitro (colony forming cells in culture or CFC) (Gwatkin et al. 1957; Lotem and Sachs 2002) (Table 1.1). As progenitor cells are stimulated to divide in response to

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