单细胞测序揭示溃疡性结肠炎中干细胞的衰老状态

Single-Cell Sequencing Reveals the Senescence State of Stem Cells in Ulcerative Colitis

目的分析溃疡性结肠炎发生发展过程中细胞类型以及基因表达的动态变化。方法采用单细胞测序技术对溃疡性结肠炎模型鼠以及正常鼠的肠道组织进行生物信息学分析。经过质控,共有58714个细胞用于构建结肠炎数据集进行下游分析,再通过降维聚类、基因本体(gene ontology,GO)分析和Monocle拟时间分析等技术手段着重分析了结肠炎发生发展过程中的上皮区室变化。结果在结肠炎样本中细胞亚群与细胞亚群间的互作关系相比于正常样本发生了明显变化。分析结果发现,大多数上皮细胞亚型在结肠炎阶段遭到破坏而数量减少。对维持干细胞功能十分重要的Wnt通路出现了抑制。Ppia(Cyclophilin A)-Bsg(Basigin)配-受体对在炎症样本中的表达降低。结论炎症状态下基质细胞分泌的Ppia耗竭导致干细胞衰老,最终扰乱上皮细胞稳态而加重结肠炎。

OBJECTIVE To analyze the dynamic changes of cell types and protein expression during the occurrence and development of ulcerative colitis.METHODS Single-cell sequencing technology was used to analyze the intestinal tissues of ulcerative colitis model mice and normal mice.After quality control,a total of 58714 cells were used to construct a colitis dataset for downstream analysis.Then,the changes of epithelial compartments in the process of colitis occurrence and development were analyzed by means of dimensionality reduction clustering,GO analysis and Monocle quasi-time analysis.RESULTS Compared with the normal samples,the interaction between cell subsets in colitis samples changed significantly.The analysis revealed that most epithelial cell subtypes were destroyed and reduced in number during the colitis phase.The Wnt pathway was inhibited,which is important for maintaining stem cell function.The Ppia-Bsg ligand receptor pair was highly expressed in normal samples.CONCLUSION The depletion of Ppia secreted by stromal cells in the inflammatory state leads to stem cell senescence,which ultimately disrupts the homeostasis of epithelial cells and aggravates colitis.