Abstract
Differentiation of oligodendroglial precursor cells (OPCs), a crucial prerequisite for central nervous system (CNS) remyelination in diseases such as Multiple Sclerosis (MS), is modulated by a multitude of extrinsic and intrinsic factors. In a previous study we revealed that the chemokine CXCL12 stimulates rodent OPC differentiation via activation of its receptor CXCR7. We could now demonstrate that CXCR7 is also expressed on NogoA- and Nkx2.2-positive oligodendroglial cells in human MS brains and that stimulation of cultured primary fetal human OPCs with CXCL12 promotes their differentiation as measured by surface marker expression and morphologic complexity. Pharmacological inhibition of CXCR7 effectively blocks these CXCL12-dependent effects. Our findings therefore suggest that a specific activation of CXCR7 could provide a means to promote oligodendroglial differentiation facilitating endogenous remyelination activities.
Highlights
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the human central nervous system (CNS), leading to gradual degeneration and loss of myelin sheaths and oligodendrocytes
Inefficient CNS remyelination observed in neuroinflammatory demyelinating diseases such as MS is tightly linked to the limited ability of resident oligodendroglial precursor cells (OPCs) to differentiate properly—a prerequisite for subsequent remyelination [5, 28]
While previous studies have demonstrated CXCR7 expression in human adult neurons [29], brain tumors [30] and human brain microvascular endothelial cells (HBMECs, [31]), we here demonstrate that CXCR7 is expressed on oligodendroglial cells in MS brain lesions and that its activation by CXCL12 leads to an acceleration of human glial maturation in culture as demonstrated by expression of oligodendrocyte lineage markers and enhanced morphological maturation
Summary
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the human central nervous system (CNS), leading to gradual degeneration and loss of myelin sheaths and oligodendrocytes. Repair activities are limited within the adult CNS, remyelination can be observed as a result of resident oligodendroglial precursor cell (OPC) activation in early disease stages. These cells can be recruited into MS lesions where they differentiate into functional myelinating cells [2]. Chemokines are highly conserved among mammalian species and regulate a plethora of different physiological processes, such as, for instance the modulation of cell-cell interactions, immune cell chemotaxis and developmental processes in a variety of tissues including the brain [7, 8]. Chemokines bind mainly to G-protein coupled receptors and exert strong effects in neuroinflammatory diseases [9, 10]. In the past the impact of chemokines on the survival and behavior
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