Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214.
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214
Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):E2885-94. doi: 10.1073/pnas.1408295111. Epub 2014 Jun 30.
Human oligodendrocyte progenitor cell (OPC) specification and differentiation occurs slowly and limits the potential for cell-based treatment of demyelinating disease. In this study, using FACS-based isolation and microarray analysis, we identified a set of transcription factors expressed by human primary CD140a(+)O4(+) OPCs relative to CD133(+)CD140a(-) neural stem/progenitor cells (NPCs). Among these, lentiviral overexpression of transcription factors ASCL1, SOX10, and NKX2.2 in NPCs was sufficient to induce Sox10 enhancer activity, OPC mRNA, and protein expression consistent with OPC fate; however, unlike ASCL1 and NKX2.2, only the transcriptome of SOX10-infected NPCs was induced to a human OPC gene expression signature. Furthermore, only SOX10 promoted oligodendrocyte commitment, and did so at quantitatively equivalent levels to native OPCs. In xenografts of shiverer/rag2 animals, SOX10 increased the rate of mature oligodendrocyte differentiation and axon ensheathment. Thus, SOX10 appears to be the principle and rate-limiting regulator of myelinogenic fate from human NPCs.
人少突胶质前体细胞（OPC）的特化和分化发生缓慢，限制了基于细胞的脱髓鞘疾病治疗的潜力。在这项研究中，我们使用基于 FACS 的分离和微阵列分析，鉴定了一组在人源 CD140a(+)O4(+) OPC 中表达的转录因子，与 CD133(+)CD140a(-)神经干细胞/祖细胞（NPC）相比。在这些转录因子中，NPC 中 ASCL1、SOX10 和 NKX2.2 的慢病毒过表达足以诱导 Sox10 增强子活性、OPC mRNA 和与 OPC 命运一致的蛋白表达；然而，与 ASCL1 和 NKX2.2 不同，只有 SOX10 感染 NPC 的转录组被诱导为人类 OPC 基因表达特征。此外，只有 SOX10 促进少突胶质细胞的分化，并且其作用水平与天然 OPC 相当。在 shiverer/rag2 动物的异种移植物中，SOX10 增加了成熟少突胶质细胞分化和轴突包绕的速度。因此，SOX10 似乎是人类 NPC 髓鞘生成命运的主要和限速调节因子。
