Regulation of Oligodendrocyte Precursor Maintenance by Chondroitin Sulphate Glycosaminoglycans
Regulation of Oligodendrocyte Precursor Maintenance by Chondroitin Sulphate Glycosaminoglycans
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DOI：
10.1002/glia.22928
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发表时间：
2016-02-01
期刊：
影响因子：
6.2
通讯作者：
Faissner, Andreas
中科院分区：
文献类型：
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作者：
Karus, Michael;Ulc, Annika;Faissner, Andreas
硫酸软骨素蛋白聚糖（CSPG）已被证明可以抑制少突胶质细胞的形态成熟以及它们的髓鞘形成能力。然而，尚不清楚CSPG和/或其各自的硫酸软骨素糖胺聚糖（CS-GAG）侧链是否也调节少突胶质细胞谱系进展。在这里，我们最初表明，CS-GAG检测的单克隆抗体473 HD表达的原代大鼠NG 2阳性少突胶质前体细胞（OPC）和O 4阳性未成熟的少突胶质细胞。CS-GAG随着少突胶质细胞的分化而下调。通过细菌酶软骨素酶ABC（ChABC）酶促去除CS-GAG链促进增殖大鼠OPCs向O 4阳性未成熟少突胶质细胞的自发分化。在强制分化后，CS-GAG的酶促去除加速了少突胶质细胞向MBP阳性和膜形成少突胶质细胞的分化。这些过程在富集的CSPG级分上减弱，主要由Phosphacan/RPTP β/zeta组成，并且在较小程度上由Brevican和NG 2组成。为了使CS-GAG有资格作为少突胶质细胞生物学的通用调节剂，我们最终测试了CS-GAG去除对来自不同来源的OPC的影响，所述不同来源例如小鼠皮质少突胶质细胞球、小鼠脊髓神经球以及最重要的人诱导的多能干细胞衍生的放射状胶质样神经前体细胞。对于所有使用的培养系统，我们观察到CS-GAG对少突胶质细胞分化的类似抑制作用。总之，这项研究清楚地表明了一个重要的基本原则，复杂的CS-GAG调节少突胶质细胞谱系的进展。此外，使用ChABC以促进少突胶质细胞向髓鞘基因表达细胞分化可能是增强白色修复的适用治疗选择。
Chondroitin sulfate proteoglycans (CSPGs) have been proven to inhibit morphological maturation of oligodendrocytes as well as their myelination capabilities. Yet, it remained unclear, whether CSPGs and/or their respective chondroitin sulfate glycosaminoglycan (CS-GAG) side chains also regulate the oligodendrocyte lineage progression. Here, we initially show that CS-GAGs detected by the monoclonal antibody 473HD are expressed by primary rat NG2-positive oligodendrocyte precursor cells (OPCs) and O4-positive immature oligodendrocytes. CS-GAGs become down-regulated with ongoing oligodendrocyte differentiation. Enzymatic removal of the CS-GAG chains by the bacterial enzyme Chondroitinase ABC (ChABC) promoted spontaneous differentiation of proliferating rat OPCs toward O4-positive immature oligodendrocytes. Upon forced differentiation, the enzymatic removal of the CS-GAGs accelerated oligodendrocyte differentiation toward both MBP-positive and membrane forming oligodendrocytes. These processes were attenuated on enriched CSPG fractions, mainly consisting of Phosphacan/RPTP beta/zeta and to less extent of Brevican and NG2. To qualify CS-GAGs as universal regulators of oligodendrocyte biology, we finally tested the effect of CS-GAG removal on OPCs from different sources such as mouse cortical oligospheres, mouse spinal cord neurospheres, and most importantly human-induced pluripotent stem cell-derived radial glia-like neural precursor cells. For all culture systems used, we observed a similar inhibitory effect of CS-GAGs on oligodendrocyte differentiation. In conclusion, this study clearly suggests an important fundamental principle for complex CS-GAGs to regulate the oligodendrocyte lineage progression. Moreover, the use of ChABC in order to promote oligodendrocyte differentiation toward myelin gene expressing cells might be an applicable therapeutic option to enhance white matter repair.