Transplanted miR-219-overexpressing oligodendrocyte precursor cells promoted remyelination and improved functional recovery in a chronic demyelinated model.
Transplanted miR-219-overexpressing oligodendrocyte precursor cells promoted remyelination and improved functional recovery in a chronic demyelinated model.
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移植的过表达 miR-219 的少突胶质细胞前体细胞促进慢性脱髓鞘模型的髓鞘再生并改善功能恢复
DOI：
10.1038/srep41407
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发表时间：
2017-02-01
影响因子：
4.6
通讯作者：
Yao RQ
中科院分区：
文献类型：
--
作者：
Fan HB;Chen LX;Qu XB;Ren CL;Wu XX;Dong FX;Zhang BL;Gao DS;Yao RQ
少突胶质前体细胞(OPC)具有通过成熟为产生髓鞘的少突胶质细胞修复脱髓鞘损伤的能力。最近的证据表明miR-219有助于调节OPC向少突胶质细胞的分化。我们使用miR-219过表达的小鼠胚胎干细胞(miR219-mESCs)进行了少突胶质细胞分化研究。以期特异性细胞标志物Nanog、Oct4、Nestin、Musashi1、GFAP、Tuj1和O4的表达分析miR219-mESCs的自我更新和多向分化特性。MIR-219可促进骨髓间充质干细胞来源的神经前体细胞向成骨细胞分化。我们进一步将来自miR219-mESCs的OPC(miR219-OPC)移植到铜酮诱导的慢性脱髓鞘小鼠中，以观察重新髓鞘形成，这导致了包含良好的少突胶质细胞移植物，这些移植物沿着痂体内迁移，成熟并表达髓鞘碱性蛋白(MBP)。超微结构研究进一步证实了新髓鞘的存在。行为测试证实，这些小鼠的认知功能得到了改善。重要的是，移植的miR219-OPC诱导了内源性NPC的增殖。综上所述，这些数据表明miR-219迅速将mESCs转化为少突胶质细胞系细胞，并且miR219-OPC的移植不仅促进了再髓鞘形成和改善认知功能，而且还促进了慢性脱髓鞘后宿主内源性NPC的增殖。这些结果支持miR-219在脱髓鞘疾病中发挥治疗作用的潜力。
Oligodendrocyte precursor cells (OPCs) have the ability to repair demyelinated lesions by maturing into myelin-producing oligodendrocytes. Recent evidence suggests that miR-219 helps regulate the differentiation of OPCs into oligodendrocytes. We performed oligodendrocyte differentiation studies using miR-219-overexpressing mouse embryonic stem cells (miR219-mESCs). The self-renewal and multiple differentiation properties of miR219-mESCs were analyzed by the expression of the stage-specific cell markers Nanog, Oct4, nestin, musashi1, GFAP, Tuj1 and O4. MiR-219 accelerated the differentiation of mESC-derived neural precursor cells (NPCs) into OPCs. We further transplanted OPCs derived from miR219-mESCs (miR219-OPCs) into cuprizone-induced chronically demyelinated mice to observe remyelination, which resulted in well-contained oligodendrocyte grafts that migrated along the corpus callosum and matured to express myelin basic protein (MBP). Ultrastructural studies further confirmed the presence of new myelin sheaths. Improved cognitive function in these mice was confirmed by behavioral tests. Importantly, the transplanted miR219-OPCs induced the proliferation of endogenous NPCs. In conclusion, these data demonstrate that miR-219 rapidly transforms mESCs into oligodendrocyte lineage cells and that the transplantation of miR219-OPCs not only promotes remyelination and improves cognitive function but also enhances the proliferation of host endogenous NPCs following chronic demyelination. These results support the potential of a therapeutic role for miR-219 in demyelinating diseases.