Emerging Cellular and Molecular Strategies for Enhancing Central Nervous System (CNS) Remyelination

Abstract

Myelination is critical for the normal functioning of the central nervous system (CNS) in vertebrates. Conditions in which the development of myelin is perturbed result in severely compromised individuals often with shorter lifespans, while loss of myelin in the adult results in a variety of functional deficits. Although some form of spontaneous remyelination often takes place, the repair process as a whole often fails. Several lines of evidence suggest it is feasible to develop strategies that enhance the capacity of the CNS to undergo remyelination and potentially reverse functional deficits. Such strategies include cellular therapies using either neural or mesenchymal stem cells as well as molecular regulators of oligodendrocyte development and differentiation. Given the prevalence of demyelinating diseases and their effects on the quality of life for affected individuals it is imperative that effective therapies are developed. Here we discuss some of the new approaches to CNS myelin repair that hold promise for reducing the burden of diseases characterized by myelin loss.

Keywords: MSCs; OPCs; demyelination; multiple sclerosis; oligodendrocytes; remyelination.

Figure 1

Structure of the myelin sheath in the central nervous system (CNS). (A) schematic diagram depicting a mature oligodendrocyte contributing to the myelin sheaths of three individual axons. Myelin sheaths are separated by bare segments of the axon, called nodes of Ranvier. Internodal myelin is shown in more detail in panel (B) where stacks of myelin are seen surrounding a segment of the axon.

Figure 2

Schematic of the major stages of development of oligodendrocytes. (A) Neural stem cells are induced by Shh to produce (B) oligodendrocyte precursor cell (OPCs), which are uniquely identified by PDGFa and NG2, among others. Differentiation of OPCs into myelinating oligodendrocytes (C,D) is associated with an increase in cellular and molecular complexity including the expression of various myelin-specific proteins and lipids.

Figure 3

Demyelination vs. remyelination. Schematic of a myelinated axon (A), in which there is oligodendrocyte dysfunction and subsequent loss of myelin sheaths. Remyelinated axons ((B); lower panel) are characterized by thin myelin sheaths. (C) Electron micrograph of axons (arrows) in the dorsal white matter of the spinal cord in an adult rat showing thin myelin sheaths (arrowheads) following lysolecithin-induced demyelination.