The aorta-gonads-mesonephros (AGM) region autonomously generates the first adult repopulating hematopoietic stem cells (HSCs) in the mouse embryo. HSC activity is initially localized to the dorsal aorta and mesenchyme (AM) and vitelline and umbilical arteries. Thereafter, HSC activity is found in the urogenital ridges (UGs), yolk sac, and liver. As increasing numbers of HSCs are generated, it is thought that these sites provide supportive microenvironments in which HSCs are harbored until the bone marrow microenvironment is established. However, little is known about the supportive cells within these midgestational sites, and particularly which microenvironment is most supportive for HSC growth and maintenance. Thus, to better understand the cells and molecules involved in hematopoietic support in the midgestation embryo, more than 100 stromal cell lines and clones were established from these sites. Numerous stromal clones were found to maintain hematopoietic progenitors and HSCs to a similar degree as, or better than, previously described murine stromal lines. Both the AM and UG subregions of the AGM produced many supportive clones, with the most highly HSCsupportive clone being derived from the UGs. Interestingly, the liver at this stage yielded only few supportive stromal clones. These results strongly suggest that during midgestation, not only the AM but also the UG subregion provides a potent microenvironment for growth and maintenance of the first HSCs. IntroductionThroughout adult life, the hematopoietic hierarchy is derived from hematopoietic stem cells (HSCs) maintained in the supportive microenvironment of the bone marrow (BM). Functional blood cells arise through a series of differentiation steps first occurring within the HSCs and proceeding through a hierarchy of progenitor cell types with increasing lineage commitment. 1-3 Both maintenance and differentiation of HSCs are controlled by complex interactions with the stromal microenvironment, 4 which consists of several morphologically distinct cell types including myofibroblasts and macrophages.Efforts to examine the interactions between HSCs and the microenvironment have led to the establishment of in vitro culture systems with adherent cells from BM. 5,6 Further studies have demonstrated that BM and fetal liver stromal cells maintain hematopoietic progenitors, long-term culture-initiating cells, cobblestone area-forming cells, and HSCs (cells capable of permanently repopulating the entire hematopoietic system of irradiated adult recipients). 7-9 Numerous stromal cell lines of adult BM and fetal liver hematopoietic microenvironments have been cloned and characterized for the growth, maintenance, and differentiation of HSCs 8-10 (see also references in Remy-Martin et al 11 ). Generally, these studies show an initial decrease in HSC activity 12 followed by an expansion phase of immature hematopoietic progenitors. 13 Most notably, the AFT024 stromal clone, derived from mouse fetal liver at day 14.5 of gestation, shows the best continued maintenance of...
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