Development and heterogeneity of macrophages and their related cells through their differentiation pathways.

Macrophages are a heterogeneous population differing in their site of location, morphology and function. They develop from hematopoietic stem cells originating in both fetal and bone marrow hematopoiesis. In yolk sac and early hepatic hematopoiesis, primitive/fetal macrophages develop from hematopoietic stem cells, bypassing the stage of monocytic cells (monoblasts, promonocytes and monocytes), possess proliferative capacity and differentiate into resident macrophages in tissues in late ontogeny. Monocytic cells develop in hepatic hematopoiesis after the development of primitive/fetal macrophages, then move into the bone marrow in late ontogeny, forming a monocyte-derived macrophage population in tissues. Like monocytes, the monocyte-derived macrophages have no proliferative potential and are short-lived, whereas the resident macrophages are long-lived in tissue, possess proliferative capacity and can be sustained by self-renewal. In adult life, the bone marrow releases macrophage precursors (immature myeloid cells) and monocytes into peripheral blood, but normally not monoblasts or promonocyts. The myeloid precursor cells migrate into tissues and differentiate into resident macrophages or related cells in situ due to macrophage differentiation or growth factors, such as M-CSF and GM-CSF, produced in situ and/or supplied humorally. Monocytes, however, migrate into tissues in response to inflammatory stimuli and differentiate into exudate macrophages. The distinct differentiation pathways of monocyte/macrophages, resident macrophages, other macrophage subpopulations, and macrophage-related cells are reviewed together with the heterogeneity of macrophage precursor cells.