During fetal development, the primary anatomical concentration of hematopoietic stem cells (HSCs) changes location several times. The migration of blood-borne progenitors is essential for the establishment of hematopoiesis in subsequent hematopoietic tissues. The speculation that this fetal migration process occurs as a series of distinct, timed developmental events, wherein large numbers of fetal HSCs simultaneously enter the bloodstream to seed newly forming hematopoietic organs, arose from observations that a decrease in HSCs and/or hematopoietic progenitor numbers in primary hematopoietic tissues occurs just prior to the seeding of newly forming hematopoietic sites. Hematopoietic precursor numbers increase in intraembryonic sites such as the aorta-gonad-mesenepheros region (AGM) and yolk sac until 11 days postconception (dpc), then decrease, becoming undetectable by 13 dpc. This decrease in HSC numbers is hypothesized to result from a wave of multipotent progenitors leaving the AGM or yolk sac to seed the fetal liver on 11 dpc. However this occurs, HSCs increase exponentially in the fetal liver from day 12 until day 15 or day 16; then, HSC numbers and activity in the fetal liver decrease, although the fetal liver HSC (FL HSC) population continues to proliferate at an equivalent rate. This decrease in HSC numbers in the fetal liver could result from a mobilization of HSCs from the fetal liver to the spleen and bone marrow. While the mechanisms that influence HSC homing and colonization are not completely understood, several experimental models suggest possible regulatory factors. The homing to and colonization of fetal hematopoietic organs by circulating HSCs likely require homing receptor/addressin interactions in the vascular lumen, followed by chemokine/chemokine receptor interactions, integrin/receptor binding, and growth/survival factors. Homing of lymphocytes and leukocytes has been well documented to involve first homing receptor/vascular addressin interactions, resulting in cell tethering and rolling on blood vessel endothelium. The rolling cells respond to a chemoattractant, produced by endothelial or stromal cells within the tissue, by firm adherence to the vessel wall mediated by integrin/receptor interactions. The adhered cells subsequently traverse the vessel wall, migrating toward the increasing gradient of chemoattractant. A similar cascade of interactions is likely to govern the migration of immature hematopoietic stem/progenitor cells. Mice born with genetic deficiency of the chemokine stromal cell-derived factor-1a (SDF-1a), or its receptor, CXCR4, fail to establish bone marrow hematopoiesis, although fetal liver hematopoiesis is normal. In addition, bone marrow HSCs (BM HSCs) have been shown to migrate selectively in vitro in response to SDF-1a. SDF-1a may be important both as a chemoattractant and as an activator of adhesion molecules on HSCs and may function in the retention and maintenance of fetal HSCs once they reach the hematopoietic niche. Correct localization of HSCs throughout ontogeny may also involve other specific interactions with the hematopoietic microenvironment. A factor that is well established to be important to the maintenance, survival and proliferation of HSCs is Steel factor (SLF). Homozygous deficiency mutations of the SLF-encoding gene (Sl), normally expressed in hematopoietic stromal cells, or its receptor gene (W), encoding the c-Kit tyrosine kinase, result in profound but incomplete defects in hematopoiesis. Functional hematopoietic cells from Steel ligand deficient mice (Sl/Sld) could be rescued by transplantation to a wild-type host. Interestingly, in the lethal Sl/Sl background, FL HSCs double their number daily between 13 and 15 dpc, indicating that factors other than SLF are responsible for fetal HSC expansion. SLF has also been implicated as a chemotactic factor of human and mouse hematopoietic progenitor cells. In order to test the hypothesis that fetal HSC migration is a timed developmental event, scientists collected blood from embryos ranging in age from 12.5 to 17.5 dpc to use in competitive reconstitution assays to measure long-term reconstituting hematopoietic stem cell (LT-HSC) activity. Results indicated that mouse fetal HSCs are found constitutively rather than episodically in fetal circulation and are present at low numbers throughout mid-to-late fetal development. Scientists also measured the seeding of the fetal spleen and fetal bone marrow during this period. The seeding of these organs is a gradual process occurring over several days and does not appear to involve a large influx of HSC. Finally, scientists found that FL HSCs migrate in response to the chemokine SDF-1a and that this response is substantially enhanced in the presence of SLF. The enhanced chemotactic response of HSCs to the combination of SLF and SDF-1a is a property of FL HSCs, but not adult BM HSCs.

An Updated Model Illustrating the Location and Relative Frequencies of Fetal HSCs in the Embryo.

HSCs are found constitutively at low numbers in fetal blood following the onset of circulation. Seeding of developing hematopoietic tissues by long-term HSCs is gradual and is not due to a large influx of cells. The large decline in HSC numbers seen in the fetal liver following 14 dpc is most likely the result of differentiation signaled by the developing hepatic environment rather than a timed migration to the fetal spleen and bone marrow.