| Hematopoietic stem cells (HSC) are rare, self-renewing cells that give rise to all the blood cell lineages. HSC are faced with several fate choices, they can self-renew, differentiate, undergo apoptosis, or migrate. The regulation of these choices is important in maintaining hematopoietic homeostasis.; Differentiation of HSC occurs through a series of steps, each resulting in loss of self-renewal capacity. We demonstrated that the up-regulation of the tyrosine kinase receptor, Flk-2, and down-regulation of the stem cell marker Thy-1.1, marks a differentiation pathway with increasing loss of self-renewal capacity. The inverse relationship between the expression of these cell surface antigens allowed us to isolate a novel multipotent progenitor population with little or no self-renewal capacity. The ability to isolate HSC committed to differentiation will allow the study of potential mechanisms involved in this cell fate decision.; We also analyzed the expression of the tyrosine kinase receptors Flk-1 (VEGF receptor 2) and Flt-1 (VEGF receptor 1) on prospectively isolated human and mouse HSC. These receptors have been reported to be markers of HSC. However, we determined by RT PCR and functional tests that neither mouse nor human HSC express these receptors.; HSC developmental decisions are likely regulated by microenvironmental factors, suggesting that HSC localization and migration play an important role in HSC biology. During fetal development HSC migrate to seed transitional hematopoietic organs. The current predominant model of fetal HSC migrations held that fetal HSC migrations occur in developmentally timed waves. In contrast to this hypothesis, we demonstrated that HSC are found constitutively at low numbers in fetal circulation throughout late fetal development. We also show that the fetal spleen and bone marrow are seeded gradually. Together, these data demonstrate that seeding of fetal organs does not require large coordinated fluxes of HSC. To begin to elucidate the mediators of bone marrow homing by fetal HSC, we evaluated their migratory response to SDF-1. Like adult HSC, fetal HSC migrate in response to SDF-1. Furthermore, the ability of fetal liver HSC to migrate in response to the SDF-1 is significantly intensified by stimulation with steel factor, indicating a synergistic effect of these factors in promoting fetal HSC migration. |
