Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany.
Ann Neurol. 2010 Dec;68(6):915-24. doi: 10.1002/ana.22214.
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.
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.
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.
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.
少突胶质前体细胞的分化对中枢神经系统（再）髓鞘形成至关重要，受多种外在和内在因素的影响。趋化因子是一组小分子，在哺乳动物中高度保守，参与发育、组织稳态和修复过程中的多种生物学过程。我们研究了趋化因子 CXCL12 是否影响少突胶质细胞，以及该分子控制哪些细胞分化/成熟过程。
使用髓鞘少突胶质细胞糖蛋白诱导实验性自身免疫性脑脊髓炎。免疫染色和定量基因表达分析用于研究两种已知的 CXCL12 受体在少突胶质细胞上的表达。对培养的原代少突胶质前体细胞进行刺激，以确定配体/受体相互作用对形态成熟和髓鞘表达的影响。进行阻断和抑制实验以揭示传递受体的身份。
该分析揭示了 CXCR4 以及 CXCR7 的存在，并且体内和体外的细胞成熟伴随着 CXCR7 的上调和 CXCR4 的下调。值得注意的是，在脱髓鞘的病变中枢神经系统中，CXCR7 表达在少突胶质细胞上得以维持，而 CXCR4 则无法检测到。然后我们证明了 CXCL12 刺激可促进培养的原代少突胶质前体细胞的形态成熟及其髓鞘表达。药理抑制 CXCR7 受体可完全阻断 CXCL12 依赖性作用。
我们的研究结果表明，CXCR7 受体的特异性激活可能为促进病变或损伤的中枢神经系统中的少突胶质细胞分化提供一种手段。
