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H ematopoiesis occurs in different organs during fetal development. Several studies suggest that the growth of hematopoietic progenitors at one stage of ontogenic maturation may not be supported by a microenvironment from a different ontogenic stage. To determine if human fetal liver (FL) clonogenic progenitors can develop in an adult bone marrow (ABM) microenvironment, we compared growth of BFU-E and CFU-GM from 7-14-wk-old FL, 11-20-wk-old fetal bone marrow (FBM), umbilical cord blood (UCB), or ABM in clonogenic medium with or without ABM stroma. In contrast to BFU-E from FBM, UCB, or ABM, soluble factor(s) produced by ABM stroma severely suppressed growth of 98% of FL BFU-E by inducing apoptosis of cells beyond early erythroblast stage. The nature of the soluble factor remains unknown, although we have evidence that it is heat labile with molecular mass < 10 kD. Antibody neutralization studies indicate that TGF-beta1, IL-1, TNF-alpha, macrophage inflammatory protein (MIP)-1alpha, or IFN-gamma are not responsible. The observation that FL progenitors may not be capable of differentiating when transferred to an ABM microenvironment may have important implications for FL transplantation into postnatal recipients. Further, this demonstrates that ontogenic stage-specific interactions between hematopoietic progenitors and their microenvironment are important for the normal development of hematopoiesis.