优化的iPS-Olig2阳性前体细胞来源的胶质细胞移植促进脊髓损伤修复的研究

重髓鞘困难和不利的胶质细胞微环境是脊髓损伤难以修复的重要外部原因。人类脊髓损伤大多属于不完全损伤。改善脊髓损伤后的胶质微环境、实现残留纤维重髓鞘化是实现脊髓损伤修复现实而有效的策略。Olig2是决定少突胶质细胞分化的关键转录因子，我们发现Olig2+细胞来源的星形胶质细胞（AS）具有强大的神经元保护作用，提示基于Olig2可获得具有强大成髓鞘能力和神经保护作用的胶质细胞亚群。本项目将建立从诱导性多潜能干细胞到Olig2+细胞，再到少突前体及AS的分化体系；进而根据文献与前期结果分选具有更强成髓鞘能力的Olig2+Zfp488+少突胶质前体亚群;采用AS细胞单克隆/神经元共培养与单细胞测序技术，鉴定具有更强神经支持作用的AS亚群，在脊髓锉伤模型中研究上述Olig2来源胶质细胞亚群移植对重髓鞘化、轴突再生、神经元存活及运动功能恢复的促进作用，以期为临床上脊髓损伤细胞治疗提供新的思路和策略。

Demyelination and harmful glial microenvironment are the two most important obstacles for repairing spinal cord injury. Most of the human spinal cord injuries are partial injury, implying that improving the glial microenvironment and achieving remyelination will provide an effective and realistic strategy for repairing the injured spinal cord. Olig2 is a key transcription factor in charging of oligodendrocyte differentiation. We found that astrocytes derived from Olig2+ cells have superior neuroprotective effects, indicating that it is able to obtain optimized glial subgroups which have stronger myelinating and neuroprotective effects. In the current project, we will establish a culture system for obtaining Olig2+ cells from induce pluripotent stem cells (iPS) cells, then sort Olig2+Zfp488+ oligodendrocyte progenitor subgroup which have stronger myelinating effect based on our data and literatures, and identify astrocyte subgroup which bear stronger neuroprotective effects using single-cell sequencing and glial cell clony/neuron co-culture. In the end, we will transplant these glial subgroups derived from Olig2+ cells into spinal contusion model, and investigate the effects on remyelination, axon regeneration, neuronal survival and locomotion recovery. This project will provide a novel cell transplantation therapy for spinal cord injury in clinic.