Single-Cell Transcriptome Analysis Reveals Six Subpopulations Reflecting Distinct Cellular Fates in Senescent Mouse Embryonic Fibroblasts.

Front Genet 2020 11;11:867. Epub 2020 Aug 11.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai, China.

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 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.

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August 2020

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