Objective: Differentiation of oligodendroglial precursor cells is crucial for central nervous system (re)myelination and is influenced by multiple extrinsic and intrinsic factors. Chemokines, a group of small proteins, are highly conserved among mammals and have been implicated in a variety of biological processes during development, tissue homeostasis, and repair. We investigated whether the chemokine CXCL12 influences oligodendrocytes and what cellular differentiation/maturation processes are controlled by this molecule.
Methods: Experimental autoimmune encephalomyelitis was induced using myelin oligodendrocyte glycoprotein. Immunostainings and quantitative gene expression analysis were used to study expression of the 2 currently known CXCL12 receptors on oligodendroglial cells. Stimulation of cultured primary oligodendroglial precursor cells was performed to determine the impact of the ligand/receptor interaction on morphological maturation and on myelin expression. Blocking and suppression experiments were conducted to reveal the identity of the transmitting receptor.
Results: This analysis revealed the presence of CXCR4 as well as CXCR7 and that cellular maturation in vivo and in vitro is accompanied by upregulation of CXCR7 and downregulation of CXCR4. Of note, in the diseased demyelinating central nervous system, CXCR7 expression is maintained on oligodendroglial cells, whereas CXCR4 could not be detected. We then demonstrated that CXCL12 stimulation promotes morphological maturation of cultured primary oligodendrocyte precursor cells as well as their myelin expression. Pharmacological inhibition of the CXCR7 receptor was shown to block CXCL12-dependent effects entirely.
Interpretation: Our findings suggest that a specific activation of the CXCR7 receptor could provide a means to promote oligodendroglial differentiation in the diseased or injured central nervous system.