Abstract
SummarySenescent 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.
Highlights
Cellular senescence is a process by which mitotically competent cells permanently arrest proliferation in response to a variety of physiological signals and pathological stresses (Munoz-Espin & Serrano, 2014)
Senescent cells secrete a myriad of inflammatory cytokines, chemokines, proteases, and growth factors that can have potent effects on tissue microenvironments (Coppe et al, 2008) and drive age-related pathologies by mechanisms that extend beyond the loss of proliferative potential
We find that (i) virtually all senescent cells display a gene expression signature that distinguishes them from their quiescent counterparts; (ii) the expression of most genes is more variable in senescent cells compared to quiescent cells; and (iii) there are correlations among genes expressed by senescent cells, including those encoding senescence-associated secretory phenotype (SASP) factors, that localize in genomic clusters
Summary
Cellular senescence is a process by which mitotically competent cells permanently arrest proliferation (growth) in response to a variety of physiological signals and pathological stresses (Munoz-Espin & Serrano, 2014). Accepted for publication 21 May 2017 cells accumulate with age, they can cause or contribute to several degenerative diseases of aging (Baker et al, 2016). These effects might stem from the fact that senescent cells cannot divide and cannot create new cells to maintain tissue homeostasis. Senescent cells secrete a myriad of inflammatory cytokines, chemokines, proteases, and growth factors that can have potent effects on tissue microenvironments (Coppe et al, 2008) and drive age-related pathologies by mechanisms that extend beyond the loss of proliferative potential
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