Diverse senescent cell populations uncovered by single-cell RNA sequencing

A new study from the National Institute on Aging, US, set out to comprehensively analyse the senescent transcriptome of human diploid fibroblasts at the individual-cell scale by performing single-cell RNA-sequencing analysis through two approaches. 

Senescence is a state of enduring growth arrest triggered by sublethal cell damage. Given that senescent cells actively secrete proinflammatory and matrix-remodelling proteins their accumulation in tissues of older persons has been linked to many diseases of aging. Despite intense interest in identifying robust markers of senescence, the highly heterogeneous and dynamic nature of the senescent phenotype has made this task difficult.

“Here, we used single-cell RNA sequencing (scRNA-seq) analysis to document both the diverse transcriptomes of human senescent fibroblasts at an individual-cell scale, and the changes in the transcriptome over time during etoposide-triggered senescence.” explained researchers: Noah Wechter, Martina Rossi, Carlos Anerillas, Dimitrios Tsitsipatis, Yulan Piao, Jinshui Fan, Jennifer L. Martindale, Supriyo De, Krystyna Mazan-Mamczarz, and Myriam Gorospe

First, the researchers characterised the different cell states in cultures undergoing senescence triggered by different stresses, and found distinct cell subpopulations that expressed mRNAs encoding proteins with roles in growth arrest, survival and the secretory phenotype.

Secondly, they characterised the dynamic changes in the transcriptomes of cells as they developed etoposide-induced senescence; by tracking cell transitions across this process, the researchers found two different senescence programs that developed divergently, one in which cells expressed traditional senescence markers such as p16 (CDKN2A) mRNA, and another in which cells expressed long noncoding RNAs and splicing was dysregulated. Finally, they obtained evidence that the proliferation status at the time of senescence initiation affected the path of senescence, as determined based on the expressed RNAs. 

“We propose that a deeper understanding of the transcriptomes during the progression of different senescent cell phenotypes will help develop more effective interventions directed at this detrimental cell population.”

The findings of this study have significant implications for our understanding of cellular senescence and its role in aging and age-related diseases. Identifying specific populations and characterising the dynamic changes in senescent cells can pave the way for the development of targeted interventions to mitigate the negative impact of senescence on health.

Further research is needed to explore the functional consequences of the distinct senescence programmes discovered in this study and their implications for therapeutic interventions. However, this study marks a crucial step forward in unravelling the complexities of cellular senescence and offers new avenues for future investigations aimed at promoting healthy aging.