Spontaneously slow-cycling subpopulations of human cells originate from activation of stress-response pathways

This topic is an example of gene-environment interactions in which the environment is either “advantageous” or “adverse,” and genes (within each individual cell), especially those controlling cell cycle, respond to these environmental signals by speeding up, or slowing down the cell cycle (i.e. cell division). Within any species, from an evolutionary perspective, individuals that give rise to the highest number of descendants or offspring are (generally) considered to be “the fittest.” However, proliferation rates among various cell types and organs/tissues are often highly variable — even in a genetically identical population under optimal growth conditions.

This heterogeneity can be seen by the presence of a small population of slow-cycling cells observed in bacteria, yeast, and even human cells. In single-celled organisms (e.g. bacteria and yeast), this heterogeneity in proliferation rate has been proposed to serve as a “bet-hedging” mechanism, in which the slow-cycling subpopulation “stands by, ready” to tolerate harsh conditions — thereby giving rise to increased fitness in a changing environment. The long-term benefit allows this heterogeneity itself to be selected as a conserved trait.

Slow-cycling cells have been implicated in resistance to antibiotics, antifungals, and chemotherapeutic drug treatment regimens, yet the origin of this slow-cycling state remains poorly understood. Authors [see attached article] isolated a naturally slow-cycling subpopulation of human cells; they found that the slow-cycling state is induced by activation of stress-response genes. Moreover, authors showed that the ability to enter this slow-cycling state protects cells from further stress — which parallels the cell’s capacity to be resistant to drugs (i.e. the adverse environmental signal).

Slow-cycling cells pass through a non-cycling period marked by low CDK2 (cyclin-dependent kinase-2) activity and high p21 (cyclin-dependent kinase inhibitor-1A) levels. Authors carried out RNA-sequencing analysis to delineate the transcriptome underlying the slow-cycling state. They discovered that cellular stress responses —the TP53 (p53; tumor protein-p53) transcriptional response, and the integrated stress response (ISR) — are the most prominent causes of spontaneous entry into the slow-cycling state. Lastly, authors showed that the cell’s ability to enter the slow-cycling state enhances its survival under stressful conditions (i.e. the slow-cycling state is ‘hardwired’ to stress responses, in order to promote cellular survival when unpredictable environments come about, e.g. sudden exposure to antibiotic or chemotherapy). Authors therefore propose that the existence of the slow-cycling state promotes long-term survival of populations that occasionally experience stressful, yet less-than-fatal environments. 😊


PLoS Biol Mar 2o19; 17: e3000178

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