A new animal study conducted by a research team from Canada and the UK has investigated whether intracerebroventricular administration of soluble chemokine fractalkine after cuprizone-induced demyelination results in increased de novo production of oligodendrocytes and in vivo remyelination from activated parenchymal oligodendrocyte precursor cells. The results demonstrated a novel pro-regenerative role of chemokine fractalkine in a demyelinating mouse model.
Multiple sclerosis (MS) is one of the most important neurological diseases, characterized by multiple areas of inflammation and demyelination in the white matter of the brain and spinal cord. The clinician manifestations are protean, being determined by the various locations and extent of the demyelinating foci. Mononuclear cell infiltration, macrophage proliferation, and loss of oligodendrocytes, myelin-producing cells characterize demyelinating lesions of the central nervous system (MS plaques).
Oligodendrocyte precursor cells are regulated by chemokines, such as neuronally secreted fractalkine (CX3CL1/FKN). Chemokines are small proteins that attract different cytokines, cells and substances to specific sites. They regulate cell positioning, and are involved in a wide range of biological processes, including homeostasis, angiogenesis, immune response, inflammation, chemotaxis, and metastases. Depending on the number of amino acids between the first two cysteine residues, the chemokines are classified into four subfamilies, CXC, CC, CX3C, and XC.
The main roles of chemokine fractalkine (CX3CL1) are promoting the binding and adhesion of leukocytes and activation of target cells. Fractalkine (CX3CL1) acts through its receptor, CX3CR1, which is expressed at high levels in microglia and at lower levels in oligodendrocyte precursor cells.
About the study
Previous works of the same research group showed that exogenous fractalkine increased myelination in small-diameter axons. It is important to note that patients with multiple sclerosis show specific neurodegeneration of small-caliber axons. However, the ability of fractalkine to promote remyelination in a demyelinating mouse model has not been tested.
The authors emphasized that previous findings suggest that fractalkine (CX3CL1/FKN) has a role in the process of remyelination. For example, demyelinated Cx3cr1 KO (knockout) and/or mice that express a human multiple sclerosis-associated CX3CR1 variant have poor remyelination, impaired microglial phagocytosis, and decreased migration and proliferation of oligodendrocyte precursor cells. The administration of exogenous soluble fractalkine before the induction of a stroke or Parkinson-like lesions resulted in neuroprotection. It seems that fractalkine CX3CR1 signaling is a critical regulator of oligodendrogenesis and myelination, and that activation of this pathway could be beneficial for remyelination.
The results demonstrated that the intracerebroventricular administration of soluble fractalkine after cuprizone-induced demyelination resulted in increased production of de novo oligodendrocytes and in vivo remyelination from activated parenchymal oligodendrocyte precursor cells in the corpus callosum and cortical gray matter. In addition, activated oligodendrocyte precursor cells and microglia/macrophages expressed fractalkine receptors CX3CR1 in vivo.
In co-culture conditions, the oligodendrocyte precursor cells and microglia needed to be stimulated with fractalkine to increase the differentiation of oligodendrocytes. This implies that fractalkine plays a role in the pro-oligodendrogenic response. A novel pro-regenerative role of fractalkine in a demyelinating mouse model suggests that fractalkine represents a new candidate for remyelination strategies.
The results of this study were published in the scientific journal Stem cell reports. de Almeida et al., Fractalkine enhances oligodendrocyte regeneration and remyelination in a demyelination mouse model. Stem Cell Reports Stem Cell Reports j Vol. 18 j 1–15 j February 14, 2023. (Open Access). https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(22)00590-2