Wu Xuan, Hu Zhechun, Yue Huimin, Wang Chao, Li Jie, Yang Yinxiang, Luan Zuo, Wang Liang, Shen Ying, Gu Yan
Center of Stem Cell and Regenerative Medicine, and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, China.
Stem Cell Res Ther. 2025 Mar 18;16(1):141. doi: 10.1186/s13287-025-04267-9.
In premature newborn infants, preterm white matter injury (PWMI) causes motor and cognitive disabilities. Accumulating evidence suggests that PWMI may result from defected differentiation of oligodendrocyte precursor cells (OPCs) and impaired maturation of oligodendrocytes. However, the underlying mechanisms remain unclear.
Using RNAscope, we analyzed the expression level of RNA-binding protein LIN28A in individual OPCs. Knockout of one or both alleles of Lin28a in OPCs was achieved by administrating tamoxifen to NG2::Ai14::Lin28a or NG2::Ai14::Lin28a mice. Lentivirus expressing FLEX-Lin28a was used in NG2 mice to overexpress LIN28A in OPCs. A series of behavioral tests were performed to assess the cognitive functions of mice. Two-tailed unpaired t-tests was carried out for statistical analysis between groups.
We found that the expression of Lin28a was decreased in OPCs in a PWMI mouse model. Knockout of one or both alleles of Lin28a in OPCs postnatally resulted in reduced OPC differentiation, decreased myelinogenesis and impaired cognitive functions. Supplementing LIN28A in OPCs postnatally was able to promote OPC differentiation and enhance myelinogenesis, thus rescuing the cognitive functions in PWMI mice.
Our study reveals that LIN28A is critical in regulating postnatal myelinogenesis. Overexpression of LIN28A in OPCs rescues cognitive deficits in PWMI mice by promoting myelinogenesis, thus providing a potential strategy for the treatment of PWMI.
在早产新生儿中，早产白质损伤（PWMI）会导致运动和认知障碍。越来越多的证据表明，PWMI可能是由少突胶质细胞前体细胞（OPCs）分化缺陷和少突胶质细胞成熟受损所致。然而，其潜在机制仍不清楚。
我们使用RNAscope分析了单个OPCs中RNA结合蛋白LIN28A的表达水平。通过对NG2::Ai14::Lin28a或NG2::Ai14::Lin28a小鼠给予他莫昔芬，实现了OPCs中Lin28a一个或两个等位基因的敲除。在NG2小鼠中使用表达FLEX-Lin28a的慢病毒在OPCs中过表达LIN28A。进行了一系列行为测试以评估小鼠的认知功能。两组之间进行双尾非配对t检验进行统计分析。
我们发现在PWMI小鼠模型中，OPCs中Lin28a的表达降低。出生后敲除OPCs中Lin28a的一个或两个等位基因会导致OPC分化减少、髓鞘形成减少和认知功能受损。出生后在OPCs中补充LIN28A能够促进OPC分化并增强髓鞘形成，从而挽救PWMI小鼠的认知功能。
我们的研究表明，LIN28A在调节出生后髓鞘形成中起关键作用。在OPCs中过表达LIN28A通过促进髓鞘形成挽救了PWMI小鼠的认知缺陷，从而为PWMI的治疗提供了一种潜在策略。
