Lineage and Development

The origin of microglial cells has been debated since the initial silver staining by del Rio-Hortega. Although most macrophages are derived from monocytes, a subset can form locally by division of preexisting macrophages or from other progenitor cells. Here two contrasting theories are discussed in support of a mesenchymal or neuroectodermal origin of microglia.

During the development of the CNS, microglial cells are found after formation of blood vessels. During the vascularization of the CNS, the penetration of the endothelial cells is followed by focal degeneration of subadjacent glial endfeet, which attract monocytes from peripheral circulation. In fact, monocytes can infiltrate the CNS and have the potential to transform into macrophagic cells, giving rise to perivascular macrophages. However, there is not enough evidence that resident mature microglia in the parenchyma are derived from monocytes. They are believed to belong to the mononuclear phagocyte system because they express Fc and CR3 receptors and are capable of phagocytosis. Furthermore, cytoplasmic enzymes expressed by microglial cells, such as lysozyme, nonspecific esterase, and peroxidase, are also found in cells of the mononuclear phagocyte system. Microglia can be identified in human fetuses as early as 13 weeks of gestation. An important accumulation of ameboid cells is observed in the ventricular zone (germinal matrix) of human fetuses at 13-24 weeks of gestation. Human fetuses less than 28 weeks of gestation also have a significant concentration of macrophages in the ventricular zone, perivascular sites, leptomeninges, and subependymal regions. However, there is no correlation between the density of the ramified micro-glia and areas where there has been a high incidence of cell death. Indisputably, hematopoietic macrophages are present and play an important role in the developing CNS. Nevertheless, as the system develops, the number of dying cells decreases, as does the number of hematopoietic macrophages. The development of ramified microglia seems to be an independent process because they appear later in development, proliferate to occupy the parenchyma, and develop close functional interactions with neurons and other glial cells.

In attempts to demonstrate that microglia can be replaced by hematopoietic monocytes, the use of bone marrow radiated chimeric animals suggests that monocytes-macrophages in leptomeninges, choroid plexus, and perivascular areas are indeed replaced by cells from the bone marrow. In contrast, parenchymal ramified microglia are not replaced by bone marrow-derived marked cells in a significant number. Thus, the majority of microglial cells come from locally present precursor cells, most likely of neuroectodermal origin. The theory of a neuroectodermal origin of microglia assumes that microglia originate from a common glial stem cell, the glioblast, in the ventricular zone and later in the subventricular zone of the developing neural tube. Thus, some of the precursor cells responsible for the turnover of macroglia might be responsible for the turnover of microglia. Another possibility is that the CNS is colonized by hematopoietic stem cells very early during development, and that stem cells become resident cells of the CNS. These cells are then responsible for the regular turnover of the intrapar-enchymal microglia in normal brain and increased numbers of microglia in pathologic conditions. To date, searches for hematopoietic stem cells in the CNS have been unsuccessful. Attempts to develop cultures of microglia initiated from the neuroepithelium of mouse embryos prior to vascularization and the appearance of monocytes-macrophages in the yolk sac strongly suggest that at least some microglial cells can originate from the neuroepithelium of the neural tube, as do other glia.

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