Determination of the origin and nature of brain macrophages and microglial cells in mouse central nervous system, using non‐radioactive in situ hybridization and immunoperoxidase techniques

Abstract

The origin and nature of brain macrophages and microglial cells in the mouse central nervous system (CNS) were investigated. First, the expression and localization of determinants recognized by the different monoclonal antibodies (mAbs) MOMA-1, Mac-1-alpha, and F4/80 (raised against cells of the mononuclear phagocyte system) were immunohistochemically studied in the developing and adult mouse brain. In order to clarify the origin of brain macrophages and microglial cells, we used bacteriophage lambda transgenic mice as donors for bone marrow transplantations in recipient mice of different ages. During ontogeny, numerous MOMA-1-, Mac-1-alpha-, and F4/80-positive blood monocyte-derived brain macrophages (amoeboid microglia) infiltrated the CNS parenchyma. These brain macrophages gradually disappeared from the brain parenchyma at postnatal day 7 (P7). From P17 on, Mac-1-alpha- and F4/80-positive cells were detected within the brain parenchyma with the morphology of resting microglial cells. Transitional forms between brain macrophages and "resting" microglia were not observed in the developing brain. Combined non-radioactive in situ hybridization and immunohistochemistry revealed many MOMA-1-positive bone marrow-derived brain macrophages that were located in the leptomeninges, the ventricles, and occasionally the blood vessel walls. These results show that brain macrophages are of bone marrow origin. Many "resting" microglial cells were detected in the brain, mainly in the white matter. It appeared that about 10% of these cells displayed the transgenic signal. This result indicates that the majority of "resting" microglial cells are of local, presumably neuroectodermal, origin.

CD163 Identifies Perivascular Macrophages in Normal and Viral Encephalitic Brains and Potential Precursors to Perivascular Macrophages in Blood

“…10,21,[63][64][65] Parenchymal microglia are derived from fetal precursors early in development and originate in the yolk sac, although it is not clear whether bone marrow elements or circulating monocytes are differentiated into parenchymal microglia (Glut-1, blue). A large number of CD163 ϩ perivascular macrophages were positive for CD14 and CD16.…”

The origin and differentiation of microglial cells during development

“…The hypothesis that microglial cells are of hemopoietic origin has been tested in mammals using bone marrow chimeras (Matsumoto and Fujiwara, 1987;Hickey and Kimura, 1988;De Groot et al, 1992;Hickey et al, 1992;Unger et al, 1993;Krall et al, 1994). One of these studies (Matsumoto and Fujiwara, 1987) failed to observe microglial cells of bone marrow origin, and concluded that microglia were probably of neuroectodermal origin.…”

“…These authors suggested that parenchymal microglia were of neuroectodermal origin, or that they derived from bone marrow-derived precursors which enter the nervous system before or about the time of birth. In an attempt to explain the presence of microglial precursors in the embryonic or early postnatal brain, De Groot et al (1992) transplanted bone marrow cells to irradiated adult and 1 day old mice. Only ca 10% of the resting microglia were of donor origin in both newborn and adult mice.…”

“…In rodents, microglial precursors seem to enter the CNS from the last days of embryonic life until the third postnatal week, and most of the microglial precursors would presumably have left the bone marrow or other hemopoietic organs by the time De Groot et al (1992) irradiated newborn mice in order to construct chimeric mice. Thus the results from bone marrow±chimeric rodents do not have still provided conclusive results regarding the origin of microglia.…”

Lung Macrophages Serve as Obligatory Intermediate between Blood Monocytes and Alveolar Macrophages

“…However, specific M⌽ populations, such as the brain microglia, have been shown to originate from local precursors, without persisting input from the BM (21). As for the origin of alveolar M⌽, although they clearly belong to the hemopoietic lineage, a direct connection to monocytic precursors remains to be shown (22).…”