Oligodendrocyte Progenitors in Glial Scar: A Bet on Remyelination

Abstract

Oligodendrocyte progenitor cells (OPCs) represent a subtype of glia, giving rise to oligodendrocytes, the myelin-forming cells in the central nervous system (CNS). While OPCs are highly proliferative during development, they become relatively quiescent during adulthood, when their fate is strictly influenced by the extracellular context. In traumatic injuries and chronic neurodegenerative conditions, including those of autoimmune origin, oligodendrocytes undergo apoptosis, and demyelination starts. Adult OPCs become immediately activated; they migrate at the lesion site and proliferate to replenish the damaged area, but their efficiency is hampered by the presence of a glial scar-a barrier mainly formed by reactive astrocytes, microglia and the deposition of inhibitory extracellular matrix components. If, on the one hand, a glial scar limits the lesion spreading, it also blocks tissue regeneration. Therapeutic strategies aimed at reducing astrocyte or microglia activation and shifting them toward a neuroprotective phenotype have been proposed, whereas the role of OPCs has been largely overlooked. In this review, we have considered the glial scar from the perspective of OPCs, analysing their behaviour when lesions originate and exploring the potential therapies aimed at sustaining OPCs to efficiently differentiate and promote remyelination.

Keywords: CNS lesion; astrocytes; demyelination; glia; multiple sclerosis; oligodendrocytes; proteoglycans; remyelination; spinal cord injury.

Figure 1

Pathological mechanisms contributing to remyelination failure in glial scar. Microglia and astrocytes contribute to the scar microenvironment by secreting pro-inflammatory CTKs, CSPGs and ROS that inhibit OPC differentiation and induce a disease-associated phenotype in OPCs and mature OLs. Disease-associated OPCs overexpress MMPs, release CSPGs and acquire phagocytic functions and astrocyte-like phenotype instead of generating new myelinating OLs. Together, all these pathological mechanisms lead to remyelination failure. OPC = oligodendrocyte precursor cells; OL = oligodendrocyte; CTK = cytokines; CSPG = chondroitin sulphate proteoglycans; ROS = radical oxygen species; MMP = matrix metalloproteinases; MHC = major histocompatibility complex. Dashed arrows indicate cell conversions. Red arrows point to events which are detrimental to remyelination. The black arrow indicates OPC maturation (i.e., transition toward a myelinating OL state).

Figure 2

Therapeutic strategies to promote remyelination and lesion resolution. (A) NPC transplantation has the potential to restore myelination and neuronal connections, replacing damaged cells. (B) Modulation of astrocyte reactivity and promotion of their transdifferentiation toward the oligodendroglial fate can reduce the levels of inhibitory factors, promoting axon regeneration and endogenous remyelination. (C) Promotion of OPC differentiation and/or inhibition of pathologically altered mechanisms aim at fostering endogenous remyelination and, in turn, protect axons from damage. NPC = Neural progenitor cell; OPC = oligodendrocyte precursor cells; OL = oligodendrocyte; CSPG = chondroitin sulphate proteoglycans.