Differentiation, Ramification and Distribution of Microglia within the Central Nervous System Examined

Abstract

The central nervous system contains several populations of mononuclear phagocytes. Principal amongst these are the tissue-resident microglia. These cells are considered to derive from circulating blood progenitors that colonise the developing human nervous system in the second trimester of fetal life. They first appear as amoeboid forms and gradually differentiate to process-bearing ‘ramified’ forms with maturation. Signals driving this transformation are known to be partly derived from astrocytes in vitro, and amoeboid microglial cells progressively ramify when co-cultured with astrocytes, mirroring the ‘differentiation’ of microglia in situ during development. In the adult, microglia occupy distinct non-overlapping territories in their ramified conformations, and are capable of ‘dedifferentiating’ to their activated amoeboid morphological states in a number of pathological circumstances. This is in keeping with the capacity of these cells for a rapid response to inflammatory cues in the CNS. The interchangeable morphological continuum of these cells supports the view that microglia represent a single heterogeneous population of resident mononuclear phagocytes capable of marked plasticity. This review will discuss signals that drive the colonisation, differentiation and ramification of microglia, and examines hypothetical models for their spatial distribution in the adult nervous system.

Microglia in the Human Nervous System during Development

“…[4][5][6]. In 1875, Eichhorst had already observed extravasating white blood cells in human embryonic spinal cords in the 4th month of gestation.…”

“…5,6]. Furthermore, the earliest forms of microglia were frequently noted to coincide with the commencement of vascular invasion of the nervous tissues.…”

“…Gradually, the latter variety increased in number, concomitant with the disappearance of amoeboid cells. There is now considerable support from studies carried out using tissue cultures [8][9][10], as well as observations in situ within the developing nervous system [5,6], for the concept of progressive differentiation of microglia. In this respect, cells possessing characteristic amoeboid macrophage-like features are observed to undergo a morphological transformation to ramified cells in response to environmental cues derived from within the CNS, and decline in numbers with the passage of time [5,6].…”

“…Subsequently, these cells penetrate the CNS parenchyma in association with the invading vasculature. The existence of a dual lineage for microglia (cells derived from fetal macrophages versus bone marrow progenitors) is a topic that is currently under debate [3,5,6,17,[27][28][29]44]. Throughout the second trimester, microglial progenitors (amoeboid migratory cells) are abundant in white matter tracts bordering nucleated structures such as the basal ganglia and thala-mus, and they subsequently invade these grey matter nuclei at later stages of development [7,26,29].…”

Microglia activation in the extremely preterm human brain

“…Microglia, the resident phagocytic cells of the central nervous system (7), take on a ramified quiescent morphology in the normal mature brain, but the active forms of intermediate and amoeboid morphologies are most common in normal developing brain (8). Activated microglia in the developing white matter are involved in eliminating transcallosal projections (9), vascularization and angiogenesis (7), myelination (10), programmed cell death, synaptic pruning (11), and axonal guidance (12).…”