Differential local tissue permissiveness influences the final fate of GPR17‐expressing oligodendrocyte precursors in two distinct models of demyelination

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.

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

“…Indeed, differentiation and maturation of OLs, full developmental axons and suitable circumstances of CNS are vital for proper myelin sheath formation (24). Mature oligodendrocytes originate from OPCs, which require the ability to proliferate, migrate and differentiate into myelinating oligodendrocytes (13,61). The differentiation or maturation of OPCs is regulated by many specific transcription factors, such as Olig1, Olig2, Mash, Myt1, Nkx2.2, Sip1, Sox10 and Mrf (25,28).…”

Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice

“…The receptor is expressed during a specific temporal window of the OPC differentiation process [18] and acts as sensor of damage, since it is abnormally upregulated in many CNS pathologies [16,17,[20][21][22]. In particular, fate mapping studies performed in GPR17-iCreER T2 :CAG-eGreen fluorescent protein (GFP) transgenic mice have shown that the pool of GPR17-expressing OPCs rapidly responds to brain injury by increasing their proliferation rate and migratory capacity, but eventually fails to accomplish terminal maturation [23][24][25]. Importantly, in vitro and in vivo data indicated that abnormal GPR17 upregulation contributes to impaired OPC maturation [26] and myelinogenesis [27], suggesting that, under pathological conditions, prolonged non-physiological over-activation of GPR17 may hamper endogenous reparative processes [28].…”

Development of the first in vivo GPR17 ligand through an iterative drug discovery pipeline: A novel disease-modifying strategy for multiple sclerosis

“…The preventive administration of compound 9 significantly delayed the symptomatic onset of EAE, suggesting the predictivity of our in silico and in vitro pipeline, which has therefore the potential to be successfully used to identify other in vivo protective compounds. Based not only on specific in silico strategy, but also on the selectivity study carried out on the 40 most similar and more phylogenetically closely related class-A GPCRs [44], we believe the beneficial effects PLOS ONE of 9 be due to a specific protective interaction with GPR17 on resident oligodendrocytes, the only cells expressing the receptor in this model [15,20]. However, since one of the main challenges for new chemical entities are the off-target effects, future studies should be also focussed on the investigation of other possible non-specific targets of this compound.…”

“…Accordingly, GPR17 overexpression in late OPCs in vitro [16] and in transgenic mice results in loss of oligodendrocytes as well as myelination arrest [15]. Its localization on the extracellular membrane of myelinating cells and its behavior in pathophysiological conditions make GPR17 an attractive 'druggable' target [11,[20][21][22][23]. Small molecules highly-selective for this receptor could be developed and used either alone or in synergy with other drugs able to control immune response and inflammation.…”