Senescent cells play important roles in both physiological and pathological processes, including cancer and aging. In all cases, however, senescent cells comprise only a small fraction of tissues. Senescent phenotypes have been studied largely in relatively homogeneous populations of cultured cells. In vivo, senescent cells are generally identified by a small number of markers, but whether and how these markers vary among individual cells is unknown. We therefore utilized a combination of single-cell isolation and a nanofluidic PCR platform to determine the contributions of individual cells to the overall gene expression profile of senescent human fibroblast populations. Individual senescent cells were surprisingly heterogeneous in their gene expression signatures. This cell-to-cell variability resulted in a loss of correlation among the expression of several senescence-associated genes. Many genes encoding senescence-associated secretory phenotype (SASP) factors, a major contributor to the effects of senescent cells in vivo, showed marked variability with a subset of highly induced genes accounting for the increases observed at the population level. Inflammatory genes in clustered genomic loci showed a greater correlation with senescence compared to nonclustered loci, suggesting that these genes are coregulated by genomic location. Together, these data offer new insights into how genes are regulated in senescent cells and suggest that single markers are inadequate to identify senescent cells in vivo.
Bibliographical noteFunding Information:
American Federation for Aging Research, (Grant / Award Number: ?Fellowship?) National Institute on Aging, (Grant / Award Number: ?AG009909?,?AG017242?,?T32-AG000266?) National Institute of Arthritis and Musculoskeletal and Skin Diseases, (Grant / Award Number: ?AR063919?) We thank Pierre-Yves Desprez for critical reading of this manuscript. This work was supported by grants from the National Institutes of Health (NIH) AG009909, AR063919 and AG017242. CW and CM were supported by NIH training grant T32-AG000266, and CW by a fellowship from the American Federation for Aging Research.
© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
- cellular senescence
- single cell