Abstract
Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17‐iCreERT2xCAG‐eGFP mice) allowing to follow the final fate of GPR17+ cells by tamoxifen‐induced GFP‐labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP+ cells at damaged areas. However, only in the cuprizone model reacting GFP+ cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP+ cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor‐1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti‐inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery.
Highlights
Oligodendroglial precursor cells (OPCs), known as NG2 cells due to their expression of the proteoglycan NG2, are known to proliferate and participate to remyelination during multiple sclerosis
Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor-1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in oligodendrocyte precursors (OPCs), leading, in turn, to differentiation blockade
Previous studies have shown that, in the brain, GPR17 acts as an intrinsic regulator of this process: it is necessary to start OPC differentiation but, after a certain stage, it has to be turned down to allow oligodendrocyte terminal maturation (Fumagalli et al, 2015; Fumagalli, Lecca, Coppolino, Parravicini, & Abbracchio, 2017)
Summary
Oligodendroglial precursor cells (OPCs), known as NG2 cells due to their expression of the proteoglycan NG2, are known to proliferate and participate to remyelination during multiple sclerosis. Promoting myelination via a specific action on key molecules involved in OPC maturation has been increasingly recognized as a promising strategy to foster endogenous remyelination, especially in the progressive forms (Rovaris et al, 2006) In this respect, the G protein-coupled receptor GPR17 has recently emerged as a key timer of oligodendrogliogenesis. In the intact brain and spinal cord, GPR17 is expressed by a subset of early bipolar NG2 positive (GPR171-NG21) OPCs, accompanies OPC maturation up to immature/pre-oligodendrocytes and is downregulated before terminal maturation (Lecca et al, 2008; Ceruti et al, 2009) Any alterations in this precise expression pattern result in myelination defects (Chen et al, 2009; Fumagalli et al, 2011; Fumagalli et al, 2015). We postulate that the inflammatory environment could be responsible for the lack of GPR17 down-regulation and the subsequent remyelination failure
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