DEVELOPMENT, DIFFERENTIATION, AND MATURATION OF KUPFFER CELLS

Primitive macrophages first develop in the murine and human yolk sac a nd then differentiate into fetal macrophages. Primitive or fetal macro phages 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. I n contrast, myelopoiesis and monocytopoiesis are not active in yolk sa c hematopoiesis and in the early stages of hepatic hematopoiesis. Prec ursor cells of primitive or fetal macrophages exist and granulocyte/ma crophage 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 m ouse stromal cell line, ST2, primitive or fetal macrophage colonies de veloped before the formation of monocyte colonies, suggesting the exis tence of a direct pathway of differentiation from primitive macrophage s into fetal macrophages during ontogeny. In severely monocytopenic mi ce induced by the administration of strontium-89, Kupffer cells have a proliferative capacity and are maintained by self-renewal. In macroph age colony-stimulating factor (M-CSF)-deficient (op/op) mice, the numb er 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 administra tion of M-CSF to op/op mice, Kupffer cells start proliferating and bec ome mature. This finding indicates that M-CSF plays an important role in the differentiation and proliferation of Kupffer cells. (C) 1997 Wi ley-Liss, Inc.