Oligodendrocyte Development and Regenerative Therapeutics in Multiple Sclerosis

Abstract

Myelination by oligodendrocytes (OLs) is an important biological process essential for central nervous system (CNS) development and functions. Oligodendroglial lineage cells undergo several morphological and molecular changes at different stages of their lineage progression into myelinating OLs. The transition steps of the oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes are defined by a specific pattern of regulated gene expression, which is under the control of coordinated signaling pathways. Any abnormal development, loss or failure of oligodendrocytes to myelinate axons can lead to several neurodegenerative diseases like multiple sclerosis (MS). MS is characterized by inflammation and demyelination, and current treatments target only the immune component of the disease, but have little impact on remyelination. Recently, several pharmacological compounds enhancing remyelination have been identified and some of them are in clinical trials. Here, we will review the current knowledge on oligodendrocyte differentiation, myelination and remyelination. We will focus on MS as a pathological condition, the most common chronic inflammatory demyelinating disease of the CNS in young adults.

Keywords: development; multiple sclerosis; myelination; oligodendrocytes; remyelination.

Figure 1

Developmental sources of oligodendrocyte progenitor cells (OPCs) and oligodendroglial cell lineage. (a) Sections of spinal cord and telencephalon showing the successive waves of oligodendrogliogenesis at different developmental stages. (b) Specification and differentiation of neural stem cells into myelinating oligodendrocytes are characterized by distinct stages, which can be identified by the acquisition and/or the disappearance of several specific markers like platelet-derived growth factor receptor (PDGFR)-α, O4 and proteolipid protein (PLP). The oligodendrocyte lineage progression is under the control of specific transcriptional factors. RP: roof plate, FP: floor plate, AEP: entopeduncular area, MGE: medial ganglionic eminence, LGE: lateral and caudal ganglionic eminences.

Figure 2

In vitro and ex-vivo models used in screening and validation assays of compounds affecting myelination. (a) Oligodendrocyte differentiation in primary rat OPCs culture. OPCs cells are obtained from P1 neonatal rat cortices and differentiated 5 days in vitro into mature oligodendrocytes expressing Sry-related HMg-Box gene 10 (Sox10, white), 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase, red) and myelin basic protein (MBP, green). Nuclei are counterstained with 4′,6-diamidino-2-phénylindole (Dapi) (bleu). (b) Organotypic cerebellar slices maintained in culture for 10 days to visualize ex-vivo myelination. Sox10 was used to stain oligodendroglia (white), MBP for myelin (green) and calbindin (CaBp) for Purkinje cells (red). Scale bars (a: 80 µm, b: 160 µm).