The Origin and Nature of Microglia

Eng-Ang Ling,     Department of Anatomy, Faculty of Medicine, National University of Singapore, Singapore, Republic of Singapore

Publisher Summary

This chapter reviews the origin and nature of miroglia. Microglial cells constitute a normal distinct cellular entity in the central nervous system and are identifiable by the silver carbonate staining method. In the past, the metamorphosis of microglia into phagocytic brain macrophages under pathological conditions or experimental lesions had received wide support from investigators. Although ameboid microglial cells display diverse morphological forms, they have many common features of monocytes and macrophages, both ultrastructurally and cytochemically. Experiments using 3H’thymidine autoradiography and carbon particles as an intracellular marker have demonstrated unequivocally that circulating monocytes give rise to ameboid microglial cells that evolve to become microglia; however, not all the ameboid microglial cells transform into microglia. The mechanism wherein the ameboid microglial cells become microglia is not clear, although it seems to coincide with the development of the corpus callosum, particularly when the axons become compact because of myelination. In neural injuries such as retrograde and Wallerian degeneration, microglial cells are reactivated to become macrophages, which would assume their phagocytic activity.

I Microglia as a Separate Cellular Entity

A Identification by Electron Microscopy

B Identification in Semithin Sections

C Terminology

D Cytochemistry of Microglia

E Distribution, Frequency, and Mitotic Activity

F Functional Role of Microglia

II Ameboid Microglia (Ameboid Cells)

A Identification in Silver Staining

B Ultrastructure

C Cytochemical Study

D Distribution and Frequency

E Mitosis and Death

III Hypotheses on the Origins of Microglia

A Mesodermal Pial Origin

B Neuroectodermal Origin

C Pericytal Origin

D Monocytic Origin

IV Recent Experimental Data

V Reappraisal of the Hypotheses on the Origins of Microglia

VI Microglia and Neural Macrophages

VII Conclusions

References

I Microglia as a Separate Cellular Entity

The first description of microglia dates back to the early part of this century, when Rio-Hortega (1919, 1932), by using a weak silver carbonate stain, succeeded in distinguishing two types of Cajal’s (quoted by Rio-Hortega, 1932) “third element” or “adendritic corpuscle,” thought to be of mesenchymal nature, in the central nervous system. Rio-Hortega noted that the two types of cells, distinctly different in their morphological and functional characteristics, were of diverse origin; he named the two types oligodendroglia and microglia. According to his original description, the oligodendroglial cell was of ectodermal (ependymal) origin, had few prolongations, and lacked phagocytic capacity, whereas the microglial cell was of mesodermal (meningeal) origin, had free and profusely branched prolongations, was endowed with migratory capacity, and showed macrophagic activities. Since then, the existence of the microglial cell as a distinct entity has been widely accepted by many authors, even before the advent of electron microscopes (Penfield, 1925, 1932; Carmichael, 1929; Dunning and Furth, 1935; Kershman, 1939; Field, 1955). In fact, the descriptions of the morphology of microglia in modern textbooks of histology and neuroanatomy have been based on Rio-Hortega’s classical observations. Thus, in sections stained with the weak silver carbonate method, microglial cells are recognized as small elements with a fusiform or stellate cell body (Fig. 1); arising from this are two or more cytoplasmic processes that in turn give rise to a variable number of secondary branches. The fullest account on microglia was by Rio-Hortega (1932), who gave a thorough review of the structure, nature, and behavior of this cell type. He further added that these cells might represent the components of the reticuloendothelial system in the central nervous system and that they were probably involved in the elimination of substances resulting from metabolism or neuronal breakdown.

Fig. 1 Evenly scattered microglial cells in the corpus callosum (A) and cerebral cortex (B) of a 22-day-old rat: Some cells are bipolar and others, multipolar. The cytoplasmic prolongations of the cells bear secondary or even tertiary branches. Silver carbonate stain. × 420.

A Identification by Electron Microscopy

Early electron microsopic studies have provided rather contradictory views as to the identity and ultrastructural morphology of microglia (Luse, 1956; Farquhar and Hartman, 1957; De Robertis and Gershenfeld, 1961; Bodian, 1964; Herndon, 1964; Yasuzumi et al., 1964). Most of these articles did not give a correct view of microglia and, in fact, created confusion. The only paper with acceptable photographs was that of Blinzinger and Hager (1962). Because most observations were poorly illustrated, some authors doubted or frankly denied the existence of microglia (Malmfors, 1963; Kruger and Maxwell, 1966; Eager and Eager, 1966; Wendell-Smith et al., 1966; King, 1968). A breakthrough in this controversial issue was provided by the work of Mori and Leblond (1969), who first adapted the weak silver carbonate method of Rio-Hortega (1919) for electron microscopy. It was reasoned that the silver deposited on the impregnated microglia should make them opaque to the electron beam. Indeed, in spite of the poor preservation of the tissue, the dense granules of silver precipitate were clearly seen over the stained cells. By correlating this method with routine electron microscopy, the identification of microglia was clarified and characterized (Mori and Leblond, 1969). Another approach was that of Blakemore (1969), who obviated the confusion between oligodendrocytes and microglia by examining such areas as periependymal zones, where oligodendrocytes were absent. Microglia can be now recognized readily in routine electron microscopy (Ling et al., 1973; Phillips, 1973; Ling and Ahmed, 1974; Blakemore, 1975; Boya, 1975; Peters et al., 1976; Fulcrand and Privat, 1977). Their consistent appearance in normal material under different fixation conditions precludes the possibility that they are fixation artifacts. The cells are characterized by a small flattened or angulated nucleus containing large dense chromatin masses that show a high contrast with the nucleoplasm (Fig. 2). The scanty cytoplasm often accumulates at one side; it is endowed with a few electron dense bodies, presumably of lysosomal nature. The Golgi apparatus is characterized by flattened and delicate saccules. The rough endoplasmic reticulum is in single isolated profiles that often course through the periphery of the cell. In addition, a centriole and microtubules may be present (Ling et al., 1973; Privat, 1975).

Fig. 2 A microglial cell from the corpus callosum of a 22-day-old rat. The cell lies between closely packed axons, of which most are unmyelinated. The elongated and flattened nucleus displays margination of dense chromatin masses. The cytoplasm that accumulates at one pole shows numerous dense bodies (db) and Golgi apparatus with characteristic thin saccules (G). The rough endoplasmic reticulum is in isolated profiles. Bar = 1 μm. (From Ling, 1976a.)

A challenge to these data came from the work of Fujita and his colleague (Fujita, 1965; Kitamura, 1973; Fujita and Kitamura, 1975, 1976), who refuted the existence of microglia as a separate cellular entity. They claimed, rather, that Rio-Hortega’s microglial cells were the products of inadequate fixation and further concluded that these cells were merely electron dense neurons, which they called “ebony neurons.” More recently,...