Single-Cell Transcriptome Analysis Reveals Six Subpopulations Reflecting Distinct Cellular Fates in Senescent Mouse Embryonic Fibroblasts
Single-Cell Transcriptome Analysis Reveals Six Subpopulations Reflecting Distinct Cellular Fates in Senescent Mouse Embryonic Fibroblasts
复制标题
单细胞转录组分析揭示了衰老小鼠胚胎成纤维细胞中反映不同细胞命运的六个亚群
DOI：
10.3389/fgene.2020.00867
复制
发表时间：
2020-08-11
影响因子：
3.7
通讯作者：
Ni, Ting
中科院分区：
文献类型：
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作者：
Chen, Wei;Wang, Xuefei;Ni, Ting
复制性衰老是衰老的一个标志，也是个体衰老的原因之一。小鼠胚胎成纤维细胞（MEFs）提供了一个方便的复制衰老模型。然而，细胞衰老过程中单个MEFs的异质性仍不清楚。在这里，我们对衰老的MEFs进行了单细胞RNA测序。主成分分析表明，这些MEFs之间存在明显的异质性，可以分为6个亚群。三种类型的基因表达分析揭示了这六个亚群不同的表达特征。轨迹分析显示，在MEF衰老过程中有三个不同的谱系。在主谱系中，一些衰老相关的分泌表型在来自衰老簇的细胞亚群中上调，这在先前的批量研究中无法区分。在另外两个谱系中，还发现了逃避细胞周期停滞的可能性以及抑制相关基因与ATP合成相关基因之间的偶联。此外，我们发现转录因子HOXD 8编码基因及其潜在的靶基因在主谱系中共表达。Hoxd8的过表达导致衰老相关的表型，表明HOXD 8是MEF衰老的新调节因子。总之，我们对衰老MEFs的单细胞测序极大地扩展了衰老研究的基本细胞模型的知识。
Replicative senescence is a hallmark of aging, which also contributes to individual aging. Mouse embryonic fibroblasts (MEFs) provide a convenient replicative senescence model. However, the heterogeneity of single MEFs during cellular senescence has remained unclear. Here, we conducted single-cell RNA sequencing on senescent MEFs. Principal component analysis showed obvious heterogeneity among these MEFs such that they could be divided into six subpopulations. Three types of gene expression analysis revealed distinct expression features of these six subpopulations. Trajectory analysis revealed three distinct lineages during MEF senescence. In the main lineage, some senescence-associated secretory phenotypes were upregulated in a subset of cells from senescent clusters, which could not be distinguished in a previous bulk study. In the other two lineages, a possibility of escape from cell cycle arrest and coupling between translation-related genes and ATP synthesis-related genes were also discovered. Additionally, we found co-expression of transcription factor HOXD8 coding gene and its potential target genes in the main lineage. Overexpression of Hoxd8 led to senescence-associated phenotypes, suggesting HOXD8 is a new regulator of MEF senescence. Together, our single-cell sequencing on senescent MEFs largely expanded the knowledge of a basic cell model for aging research.