Regulation of fetal liver erythropoiesis

Abstract

The liver is the main erythropoietic tissue of the human fetus at midterm. The regulatory mechanisms involved in red cell formation should explain three main aspects of fetal erythropoiesis. First, the initiation of erythropoiesis during the formation of the embryonic liver from the hepatic endoderm. Second, the conservation of a high erythropoietic activity in the fetal liver for several weeks until achievement of a fully developed bone marrow. And third, the switch mechanism from fetal hemoglobin to adult hemoglobin. There is experimental evidence for the induction of red cell formation in cells of the hepatic mesenchyme due to the interaction of these cells with the liver parenchymal cells. The nature of the factors involved in this process remain to be investigated but it has been found that at least one of them may be erythropoietin, a protein actively synthesized in cultures of fetal hepatocytes. Erythropoietin has been found in the fetal serum of mammals but seems to play a role late in the erythropoietic development of the liver. Liver erythroid cells isolated from young fetuses (8–12 weeks of gestation) show a poor response towards erythropoietin when compared with cells isolated from older fetuses. This observation suggests the involvement of other factors different from erythropoietin at early gestation. One of these factors is testosterone which stimulates heme and hemoglobin synthesis in liver cells isolated from fetuses of 10–13 weeks of gestation. Another set of factors are the hormones which interact with cellular β-andrenergic receptors. These factors act to regulate red cell formation in cells of fetuses obtained at 8 and 11 weeks of gestation. The switch mechanism from fetal to adult hemoglobin remains one of the main unresolved problems of fetal erythropoiesis. Erythropoietin does not change the ratios of fetal to adult hemoglobin in cell cultures of human fetal liver. Testosterone and estradiol added to these cells in vitro can change the ratio of both hemoglobins but since the change is small these steroid hormones may play only a secondary role in the switch mechanism of globin chains. The fetal lamb seems to have a switch mechanism different from the human because experimental bleeding (to increase erythropoietin concentration) elevates the adult hemoglobin levels. It has been suggested that in the sheep the regulation of adult hemoglobin synthesis (α 2β 2) may be indirectly controlled by an imbalance of γ to α chain mRNA's, which may change from 2 to 1 at early gestation to a ratio of 1:1 after 100 days of gestation. If a similar mechanism is operative in man remains to be investigated.