Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis

Abstract

Oligodendrocytes readily regenerate and replace myelin membranes around axons in the adult mammalian central nervous system (CNS) following injury. The ability to regenerate oligodendrocytes depends on the availability of neural progenitors called oligodendrocyte precursor cells (OPCs) in the adult CNS that respond to injury-associated signals to induce OPC expansion followed by oligodendrocyte differentiation, axonal contact and myelin regeneration (remyelination). Remyelination ensures the maintenance of axonal conduction, and the oligodendrocytes themselves provide metabolic factors that are necessary to maintain neuronal integrity. Recent advances in oligodendrocyte regeneration research are beginning to shed light on critical intrinsic signals, as well as extrinsic, environmental factors that regulate the distinct steps of oligodendrocyte lineage progression and myelin replacement under CNS injury. These studies may offer novel pharmacological targets for regenerative medicine in inflammatory demyelinating disorders in the CNS such as multiple sclerosis. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.

Keywords: Inflammation; Multiple sclerosis; Myelin; Oligodendrocyte precursor cells; Oligodendrocytes; Regeneration; Remyelination.

Figure 1

Negative modulators of remyelination include Notch, Wnt, Lingo, and Semaphorin signaling as well as extracellular debris. Positive modulators of remyelination include muscarinic acetylcholine receptor (mAChR) and retinoid X receptor (RXR) signaling. Remyelination efficiency is also dependent on extrinsic factors, including those secreted by classically activated (CAM) and alternatively activated (AAM) macrophages/microglia, and a balance between CAM and AAM appears to modulate the regenerative process. Since myelin is necessary for saltatory conduction and oligodendrocytes provide metabolic support to neurons, chronic demyelination and oligodendrocyte loss in MS are likely to contribute to axonal dystrophy and progressive neurodegeneration.