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Quetiapine induces oligodendrocyte precursor cell differentiation by cholesterol biosynthesis

ABSTRACT: Multiple sclerosis (MS) is characterized by demyelinated lesions in the central nervous system. Destruction of myelin and secondary damage to axons and neurons leads to significant disability, particularly in people with progressive MS. Accumulating evidence suggests that the potential for myelin repair exists in MS, although for unclear reasons this process fails. The cells responsible for producing myelin, the oligodendrocytes, and their progenitors oligodendrocyte precursor cells (OPCs) have been identified at the site of lesions, even in adults. Their presence suggests the possibility that endogenous remyelination without transplantation of donor stem cells may be a strategy for myelin repair in MS. Strategies to develop novel therapies have focused on induction of signaling pathways that stimulate OPCs to mature into myelin-producing oligodendrocytes that could then possibly remyelinate lesions. We have been investigating pharmacological approaches to enhance OPC differentiation, and have identified that the combination of two agents, triiodothyronine (T3) and quetiapine, leads to an additive effect on OPC differentiation and consequent myelin production via both overlapping and distinct signaling pathways. While the ultimate production of myelin requires cholesterol biosynthesis, we identified that quetiapine enhances gene expression in this pathway more potently than T3. Two blockers of cholesterol production, betulin and simvastatin, reduced OPC differentiation into myelin producing oligodendrocytes. Elucidating the nature of agents that lead to complementary and additive effects, possibly even synergistic effects, on oligodendrocyte differentiation and myelin production may pave the way for more efficient induction of remyelination in people with MS.

ORGANISM(S): Rattus rattus Rattus norvegicus

PROVIDER: GSE125325 | GEO | 2019/07/30

REPOSITORIES: GEO

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Project description:In multiple sclerosis (MS) and experimental models of demyelination, myelin repair is mostly achieved by oligodendrocyte precursor cells (OPCs). To gain insight into the biological specificity of these adult precursors, in the perspective to better understand why remyelination often fails in MS, we performed a micro-array analysis on purified populations of murine OPCs and oligodendrocytes. We demonstrated that, in a control environment, M-bM-^@M-^\quiescentM-bM-^@M-^] adult OPCs are more mature than neonatal OPCs, with a mRNA profile closer to oligodendrocytes. However, when demyelination occurs, adult OPCs revert to an immature gene expression profile, acquiring higher migration and faster differentiation capacities. Among the many genes differentially regulated by these M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs, genes of the innate immune response, IL1M-NM-2 and CCL2 were strongly upregulated after demyelination, with increased protein expression in experimental demyelinating lesions and within MS plaques. We first showed in vitro that both IL1M-NM-2 and CCL2 M-bM-^@M-^\accountM-bM-^@M-^] for increased migration capacities of adult OPCs, an effect that is suppressed by corresponding receptor blockade. Focusing on Ccl2, we then demonstrated that lentiviral over-expression of Ccl2 increases motility of M-bM-^@M-^\quiescentM-bM-^@M-^] adult OPCs, which become as mobile as M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs. This in vitro gain of function was further confirmed in vivo, by showing an increased migration of grafted CG4 oligodendroglial cells over-expressing-Ccl2. These results, demonstrating that M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs upregulate immune cues favouring their migration, open new perspective of demyelination-induced immune-glial interactions, which might influence both oligodendroglial and inflammatory cells, therefore play a key role in lesion fate in multiple sclerosis. In this study, we loaded purified population of progenitors of oligodendrocytes (OPCs) (from neonatal, 2-month-old, 2-month-old and cuprizone-treated brains) and of mature oligodendrocytes (OLs) (2-month-old brains) and compared their gene expression. We compared gene expression of neonatal OPCs, adult OPCs, adult OLs and adult OPCs from control conditions and from demyelinating conditions, using 3 to 4 independant replicates in each group.

Project description:Astrocytes are instrumental in both maintaining CNS homeostasis and responding to tissue injury. While astrocyte activation may be a beneficial response to acute pathologies, prolonged reactive gliosis is thought to be injurious in neurodegenerative diseases, including multiple sclerosis (MS). A major limitation of studying neurodegenerative diseases is lack of human pathological specimens obtained during the acute stages, thereby relegating research to post mortem specimens often obtained years after the initiation of pathology. Rodent reactive astrocytes have been shown to be cytotoxic to neurons and oligodendrocytes but may differ from human cells, especially in diseases with known genetic susceptibility. Herein, we purified human CD49f+ astrocytes from differentiated induced pluripotent stem cells derived from individual patient and control peripheral white blood cell samples. We compared TNF and IL1a stimulated human reactive astrocytes from 7 persons with MS and 6 non-MS controls and show their specific astrocyte transcriptomic profiles are remarkably similar to those described in rodents. The functional effect of astrocyte conditioned media (ACM) was examined in a human oligodendrocyte precursor cell (OPC) line differentiation assay using a transgenic secreted reporter of myelin basic protein (MBP) expression. ACM was not cytotoxic to the OPCs but robustly inhibited the MBP reporter. No differences were seen between MS and control stimulated astrocytes at either the transcript level or in functional OPC suppression assays. We next used RNAseq to interrogate differentially expressed genes in the OPC lines that had suppressed differentiation from the human ACM. Remarkably, not only was OPC differentiation and myelin gene expression suppressed, but we observed induction of several immune pathways and Nf-κB signaling in OPCs exposed to the ACM. These data support the notion that reactive astrocytes can inhibit OPC differentiation thereby limiting their remyelination capacity, and that OPCs take on an immune profile in the context of inflammatory cues.

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Quetiapine induces oligodendrocyte precursor cell differentiation by cholesterol biosynthesis

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