Disparate regulation of human fetal erythropoiesis by the microenvironments of the liver and bone marrow

The liver and the bone marrow (BM) are the major organs that support hemato poiesis in the human fetus. Although both tissues contain the spectrum of h ematopoietic cells, erythropoiesis dominates the liver. Previous studies su ggested that a unique responsiveness of fetal burst-forming units erythroid (BFU-E) to erythropoietin (EPO) obviates the need for cytokines with burst -promoting activity (BPA) in fetal erythropoiesis. This potential regulator y mechanism whereby fetal erythropoiesis is enhanced was further investigat ed. Fluorescence-activated cell sorting was used to isolate liver and BM pr ogenitors based on their levels of CD34 and CD38 expression. The most matur e population of CD34(+) lineage (Lin)(-) cells was also the most prevalent of the three subpopulations and contained BFU-E responsive to EPO alone und er serum-deprived conditions. Kit ligand (KL) also strongly synergized with EPO in stimulating the growth of these BFU-E. An intermediate subset of CD 34(++)CD38(+)Lin(-) cells contained erythroid progenitors responsive to EPO alone, but also displayed synergism between EPO and KL, granulocyte-macrop hage colony-stimulating factor (GM-CSF), or interleukin (IL)-3, demonstrati ng that erythroid progenitors that respond to cytokines with BPA do exist i n fetal tissues as in the adult BM. Candidate stem cells (CD34(++)CD38(-)Li n(-) cells) did not respond to EPO. Synergisms among KL, CM-CSF, and IL-3, and to a lesser extent granulocyte colony-stimulating factor (G-CSF) and FL K-2/FLT-3 ligand (FL), supported the growth of primitive multipotent progen itors that became responsive to EPO. These data define the limits of EPO ac tivity in fetal erythropoiesis to cells that express CD38 and demonstrate t he potential for various cytokine interactions to be involved in regulating fetal erythropoiesis. Furthermore, a comparison of the responses of liver and BM erythroid progenitors revealed similarly in their responses to cytok ines but a difference in the frequency of BFU-E among the three subpopulati ons examined. A. higher frequency of BFU-E among the intermediate and late progenitor subsets in the liver indicates that regulatory factors acting on stem cells and their immediate progeny are partially responsible for the h igh content of erythropoiesis in the liver. These data implicate a critical role for the microenvironments of the liver and BM in regulating the dispa rate levels of erythropoiesis in these tissues. (C) 2001 Academic Press.