Primitive macrophages first develop in the murine and human yolk sac and then differentiate into fetal macrophages. Primitive or fetal macrophages enter the blood stream and migrate into the fetal liver. Fetal macrophages possess a high proliferative capacity and express antigens and peroxidase activity of resident macrophages with the progress of gestation; they become mature and then transform into Kupffer cells. In contrast, myelopoiesis and monocytopoiesis are not active in yolk sac hematopoiesis and in the early stages of hepatic hematopoiesis. Precursor cells of primitive or fetal macrophages exist and granulocyte/macrophage colony-forming cells develop in the yolk sac and in the early stages of fetal liver development, whereas macrophage colony-forming cells emerge and increase later in fetal liver development. In vitro, similar colonies were formed from each fetal hematopoietic cell in the presence of different macrophage growth factors. During culturing of the yolk sac cells and hepatic hematopoietic cells on a monolayer of mouse stromal cell line, ST2, primitive or fetal macrophage colonies developed before the formation of monocyte colonies, suggesting the existence of a direct pathway of differentiation from primitive macrophages into fetal macrophages during ontogeny.
In severely monocytopenic mice induced by the administration of strontium-89, Kupffer cells have a proliferative capacity and are maintained by self-renewal. In macrophage colony-stimulating factor (M-CSF)-deficient (op/op) mice, the number of Kupffer cells is reduced, and they are characterized by immature morphology and a proliferative potential similar to that of primitive or fetal macrophages during ontogeny. Immediately after the administration of M-CSF to op/op mice, Kupffer cells start proliferating and become mature. This finding indicates that M-CSF plays an important role in the differentiation and proliferation of Kupffer cells.