单细胞RNA测序揭示星形胶质细胞的异质性

Single-cell RNA sequencing reveals the heterogeneity of astrocytes

背景:星形胶质细胞是中枢神经系统含量最丰富的细胞,存在多种亚型具有很强的异质性,执行着多种特殊功能。近年来,单细胞RNA测序技术从转录组分析的角度扩展了人们对星形胶质细胞异质性的理解。目的:综述单细胞RNA测序技术对星形胶质细胞在不同物种、不同时空以及不同疾病状态异质性研究的进展,扩展对星形胶质细胞异质性在分子和功能层面的认识。方法:检索PubMed、Elsevier及中国知网数据库收录的星形胶质细胞异质性及单细胞RNA测序研究相关文献,中文检索词为“星形胶质细胞、单细胞RNA测序、异质性、阿尔茨海默综合征、脊髓损伤、多发性硬化症”;英文检索词为“astrocytes,scRNA-seq,heterogeneity,Alzheimer disease,spinal cord injury,multiple sclerosis”等,经过入组标准筛选,最终纳入74篇文献进行综述。结果与结论:星形胶质细胞的单细胞RNA测序相关研究显示,星形胶质细胞在不同物种、发育阶段、中枢神经系统区域和病理状态4个方面均存在明显的异质性。①不同物种的星形胶质细胞出现某些基因的独特表达,物种特异基因的发现对临床研究的转化大有裨益。②在星形胶质细胞发育过程中,各阶段鉴定出的细胞亚型出现了基因的差异表达,这进一步细化了星形胶质细胞的细胞谱系,为星形胶质细胞发育轨迹和机制的研究奠定基础。③差异基因表达的发现可以对不同星形胶质细胞亚群进行区域定位,为构建“细胞图谱”做出贡献,为神经疾病的诊疗提供帮助。④单细胞RNA测序揭示的星形胶质细胞异质性可以在疾病诊断时提供特异性标志,发现潜在的治疗靶点。⑤星形胶质细胞异质性存在于多个方面,交互且复杂,其产生、维持和转化的机制尚不清楚,目前在单细胞水平上的分子研究仍缺乏,将转录定义的星形胶质细胞亚群与细胞活动、行为和疾病标志实时联系起来仍然是该领域的巨大挑战之一。

BACKGROUND:Astrocytes are the most abundant cells in the central nervous system,and various subsets of astrocytes are heterogeneous,performing a variety of special functions.Single-cell RNA sequencing(scRNA-seq)technology developed in recent years has extended our understanding of astrocyte heterogeneity from the perspective of transcriptome profiling.OBJECTIVE:To summarize the heterogeneity of scRNA-seq technology in different time and space,and pathological states and expand our knowledge of astrocyte heterogeneity on both molecular and functional levels.METHODS:The relevant articles on astrocyte heterogeneity and scRNA-seq were searched on PubMed,Elsevier,and CNKI databases.The search terms were“astrocytes,scRNA-seq,heterogeneity,Alzheimer disease,spinal cord injury,multiple sclerosis”in Chinese and English.Finally,74 articles were selected for viewing after screening according to inclusion criteria.RESULTS AND CONCLUSION:scRNA-seq studies related to the heterogeneity of astrocytes have shown that astrocyte is significantly heterogeneous across four aspects:species,developmental stage,central nervous system region,and pathological state.(1)Unique expression of certain genes occurs in astrocytes of different species,and the discovery of species-specific genes is beneficial for the translation of clinical studies.(2)During astrocyte development,differential gene expression emerged in the cellular subtypes identified at each stage,which further refined the cellular lineage of astrocytes and laid the foundation for the study of astrocyte developmental trajectories and mechanisms.(3)The discovery of differential gene expression allows regional localization of different astrocyte subpopulations and assists in the diagnosis and treatment of neurological diseases.(4)Astrocyte heterogeneity revealed by scRNA-seq can provide specific markers at the time of disease diagnosis and identify potential therapeutic targets.(5)The heterogeneity of astrocytes exists in many aspects,interacts with each other and is complex.The mechanisms of its generation,maintenance and transformation remain unclear.At present,molecular research on the single-cell level is still lacking.Linking transcriptionally defined astrocyte subpopulations to cellular activity,behavior and disease markers in real time remains one of the great challenges in the field.