Abstract
In multiple sclerosis (MS), oligodendrocyte precursor cells (OPCs) are recruited to the site of injury to remyelinate damaged axons; however, in patients this process is often ineffective due to defects in OPC maturation. The membrane receptor GPR17 timely regulates the early stages of OPC differentiation; however, after reaching its highest levels in immature oligodendrocytes, it has to be downregulated to allow terminal maturation. Since, in several animal models of disease GPR17 is upregulated, the aim of this work was to characterize GPR17 alterations in MS patients. We developed immunohistochemistry and immunofluorescence procedures for the detection of GPR17 in human tissues and stained post-mortem MS brain lesions from patients with secondary progressive MS and control subjects. The inflammatory activity in each lesion was evaluated by immunohistochemistry for the myelin protein MOG and the HLA antigen to classify them as active, chronic inactive or chronic active. Hence, we assessed the distribution of GPR17-positive cells in these lesions compared to normal appearing white matter (NAWM) and white matter (WM) of control subjects. Our data have shown a marked increase of GPR17-expressing oligodendroglial cells accumulating at NAWM, in which moderate inflammation was also found. Furthermore, we identified two distinct subpopulations of GPR17-expressing oligodendroglial cells, characterized by either ramified or rounded morphology, that differently populate the WM of healthy controls and MS patients. We concluded that the coordinated presence of GPR17 in OPCs at the lesion sites and inflamed NAWM areas suggests that GPR17 could be exploited to support endogenous remyelination through advanced pharmacological approaches.
Highlights
Introduction published maps and institutional affilOligodendrocyte precursor cells (OPCs) participate to remyelination under both physiological and pathological conditions by differentiating to mature, myelin producing cells.In multiple sclerosis (MS), this process is often impaired, resulting in blockade of oligodendroglial differentiation and inadequate myelin repair, with consequent alterations of impulse transmission, axonal damage, and neurodegeneration [1]
We concluded that the coordinated presence of GPR17 in oligodendrocyte precursor cells (OPCs) at the lesion sites and inflamed normal appearing white matter (NAWM) areas suggests that GPR17 could be exploited to support endogenous remyelination through advanced pharmacological approaches
In samples deriving from patients with MS, we identified a total of 69 demyelinating lesions: 26 in white matter (WM) and 43 in grey matter
Summary
Introduction published maps and institutional affilOligodendrocyte precursor cells (OPCs) participate to remyelination under both physiological and pathological conditions by differentiating to mature, myelin producing cells.In multiple sclerosis (MS), this process is often impaired, resulting in blockade of oligodendroglial differentiation and inadequate myelin repair, with consequent alterations of impulse transmission, axonal damage, and neurodegeneration [1]. Despite a recent study indicated that the oligodendroglial differentiation block is not due to intrinsic oligodendroglial factors, but rather caused by the inflammatory environment inside the lesions [2], anti-inflammatory drugs alone are not sufficient to bypass this block, suggesting that their combination with pro-remyelinating agents may represent the road to the therapeutic success. To address this issue, various molecular pathways regulating OPC maturation are under investigation, especially for the progressive forms [3].
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