Astrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions

Abstract

Myelination is an essential process that consists of the ensheathment of axons by myelin. In the central nervous system (CNS), myelin is synthesized by oligodendrocytes. The proliferation, migration, and differentiation of oligodendrocyte precursor cells constitute a prerequisite before mature oligodendrocytes extend their processes around the axons and progressively generate a multilamellar lipidic sheath. Although myelination is predominately driven by oligodendrocytes, the other glial cells including astrocytes and microglia, also contribute to this process. The present review is an update of the most recent emerging mechanisms involving astrocyte and microglia in myelin production. The contribution of these cells will be first described during developmental myelination that occurs in the early postnatal period and is critical for the proper development of cognition and behavior. Then, we will report the novel findings regarding the beneficial or deleterious effects of astroglia and microglia, which respectively promote or impair the endogenous capacity of oligodendrocyte progenitor cells (OPCs) to induce spontaneous remyelination after myelin loss. Acute delineation of astrocyte and microglia activities and cross-talk should uncover the way towards novel therapeutic perspectives aimed at recovering proper myelination during development or at breaking down the barriers impeding the regeneration of the damaged myelin that occurs in CNS demyelinating diseases.

Keywords: astrocyte; microglia; myelination; oligodendrocyte; remyelination.

Figure 1

Major roles of astrocytes and microglia during developmental oligodendrogenesis and myelination. The different steps of oligodendroglial cell production (purple) are shown and include oligodendrocyte progenitor cell (OPC) migration, proliferation, differentiation as well as the maturation of immature oligodendrocytes into cells able to myelinate neuronal axons. Astrocyte- (A) and microglia- (B) derived molecules are indicated. The green arrows indicate molecules exhibiting a positive activity on oligodendrocyte lineage and myelin production (top in each panel) whereas the red arrows and blocking symbols indicate molecules displaying an inhibiting activity on oligodendroglial lineage production (bottom in each panel).

Figure 2

Reactive astrocyte-derived secretion products during myelin repair. The oligodendroglial lineage is shown in purple. Reactive astrocytes generate molecules promoting (top, green arrows) or blocking (bottom, red arrows and blocking symbols) myelin regeneration. Besides reactive astrocytes, two additional forms of astrocytes are indicated including myelin-laden astrocytes endowed with a deleterious effect under inflammatory conditions and transplanted immature astrocytes which promote OPC proliferation/differentiation and additionally prevent glial scar formation.

Figure 3

Key effects of microglia/macrophages during myelin repair. (A) Illustration of morphological modifications of ramified microglia/macrophages, which adopt a rhomboid shape in the presence of any insult and become activated into a classical or alternative manner giving rise to a range of cell phenotypes expressing mostly pro- (red) or anti-inflammatory (green) molecules, respectively. (B) Phagocytosis of myelin debris is a critical activity of microglia/macrophages for promoting myelin regeneration. Phagocytic receptors such as CR3 advance phagocytosis by promoting the activation of paxillin and cofilin whereas the immune inhibitory receptor SIRPα, inhibits phagocytosis by promoting the inactivation of the two. Recruited by CR3, Syk downregulates CR3-mediated myelin phagocytosis protecting phagocytes from excessive phagocytosis during prolonged exposure to debris. (C) Pro-regenerative microglia secrete a range of molecules intervening at various steps of myelin repair.