Restoring the balance between disease and repair in multiple sclerosis: insights from mouse models

Abstract

Multiple sclerosis (MS) is considered an autoimmune-mediated demyelinating disease that targets the central nervous system (CNS). Despite considerable research efforts over multiple decades, our understanding of the basic biological processes that are targeted in the disease and the mechanisms of pathogenesis are poorly understood. Consequently, current therapies directed at controlling the progression of the disease are limited in their effectiveness. Historically, the primary focus of MS research has been to define the cellular and molecular basis of the immunological pathogenic mechanisms. Recently, however, it has become clear that long-term functional recovery in MS will require the development of strategies that facilitate myelin repair in lesion areas. The emerging evidence that the adult vertebrate CNS retains the capacity to regenerate neural cells that have been lost to disease or damage has provoked intensive research focused on defining the mechanisms of myelin repair. Unfortunately, the existing animal models of MS are poorly equipped to assess myelin repair, and new validated strategies to identify therapeutics targeted at promoting myelin repair are badly needed. This Commentary will review established murine models of MS, and discuss emerging technologies that promise to provide insights into the mechanisms of myelin repair.

Fig. 1.

Origin and function of oligodendrocytes, and immunological basis of MS. Myelin, the fatty insulation that wraps around axons in the vertebrate central nervous system, is produced by oligodendrocytes. During development oligodendrocytes are generated from neural stem cells (NSCs) that in specific locations commit to an oligodendrocyte lineage. Oligodendrocyte precursor cells (OPCs) then proliferate and migrate widely as they mature through a series of stages regulated by distinct signals before myelinating their target axons. Each oligodendrocyte can myelinate internodes on multiple axons; the precise number of axons myelinated by a single oligodendrocyte depends on axonal size and location. In autoimmune-mediated demyelinating diseases such as MS, T cells targeted against myelin proteins are stimulated to enter the CNS where they damage the myelin, resulting in demyelination, oligodendrocyte death and loss of axonal function. Ideal therapeutics should enhance the formation of oligodendrocytes from OPCs and inhibit the destructive functions of T cells.

Fig. 2.

In mouse models of MS, myelin repair can occur alongside demyelination. Axons surrounded by degenerating myelin (arrows) are frequently found adjacent to demyelinated axons (asterisks) and in close proximity to axons that are undergoing remyelination, as demonstrated by the presence of newly formed thin myelin sheaths (arrowheads), suggesting that functional deficits represent the balance between tissue damage and repair. Bar, 20 μm.

Fig. 3.

The pivot point model for CNS-demyelinating diseases. In this model, normal conditions characterized by a lack of functional deficits (A) do not necessarily represent a total absence of pathogenic pressure but rather that the pressure resulting from injury or disease is effectively counteracted by the pressure of repair, resulting in a balance point and lack of detectable functional deficits. (B) Disease states occur when the pathogenic pressure overwhelms the pressure of repair, as a result of either elevated pathogenesis or reduced repair, resulting in functional deficits. (C) Effective treatments aim to re-establish the balance point by reducing pathogenic pressure or enhancing repair, or ideally both.