Abstract
Myelin sheaths in the central nervous system (CNS) insulate axons and thereby allow saltatory nerve conduction, which is a prerequisite for complex brain function. Multiple sclerosis (MS), the most common inflammatory autoimmune disease of the CNS, leads to the destruction of myelin sheaths and the myelin-producing oligodendrocytes, thus leaving behind demyelinated axons prone to injury and degeneration. Clinically, this process manifests itself in significant neurological symptoms and disability. Resident oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) are present in the adult brain, and can differentiate into mature oligodendrocytes which then remyelinate the demyelinated axons. However, for multiple reasons, in MS the regenerative capacity of these cell populations diminishes significantly over time, ultimately leading to neurodegeneration, which currently remains untreatable. In addition, microglial cells, the resident innate immune cells of the CNS, can contribute further to inflammatory and degenerative axonal damage. Here, we review the molecular factors contributing to remyelination failure in MS by inhibiting OPC and NSC differentiation or modulating microglial behavior.
Highlights
Aside from multifocal inflammation and demyelination, neurodegeneration is one of the hallmarks of multiple sclerosis (MS)
While the past years have seen the approval of highly potent immunomodulatory drugs which led to a paradigm shift in the treatment of relapsing subtypes of MS (RMS), therapies that stimulate myelin repair and prevent neurodegeneration are still unavailable
And probably due to their proximity to mature myelin-forming oligodendrocytes, clinical research has so far exclusively focused on molecules stimulating the differentiation of oligodendroglial precursor cells (OPCs)
Summary
Aside from multifocal inflammation and demyelination, neurodegeneration is one of the hallmarks of multiple sclerosis (MS). Anti-RGMa treatment leads to a decreased T cell proliferation, a decrease in pro-inflammatory interleukin production, a functional recovery in experimental autoimmune encephalomyelitis (EAE) [39] and to a prolonged conversion time to the secondary progressive disease phase [40] Opicinumab, another monoclonal antibody, was investigated in several clinical trials assessing its effectiveness and safety in MS patients. In some of these studies, more NSC-derived than OPC-derived newly generated oligodendrocytes were detected [64,65], pointing to the relevance of these cells regarding CNS repair As these studies identified NSCs as a major contributing source for myelin repair, the question arises why NSC-mediated remyelination in MS is overall inefficient and even decreases over time. Measurements of 14 C incorporation into genomic DNA (a result of nuclear tests during the Cold War) demonstrated that newly generated oligodendrocytes can still be detected around the lateral wall of the adult human SVZ [74], thereby providing evidence for ongoing oligodendrogenesis in the adult
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