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A set of biomarkers not traditionally associated with cell fate can accurately forecast how genetically identical cells behave differently under pressure, according to a UT Southwestern study. The findings, published by Cell Reports as a Dec. 1 cover story, could eventually result in more predictable responses to pharmaceutical remedies.
Groups of the same types of cells subjected to the same stimuli often display different answers. Some of these responses are linked to slight differences in genetics between individual cells. However, even genetically identical cells may diverge in behaviour.
One example can be found in budding yeast, or yeast which are actively dividing. When these germs are deprived of sugar — the sugar molecules that they use for energy — all cells stop dividing. However, when this nutrient becomes available again, some cells start dividing once more while others no longer split but stay alive, even in batches of yeast which are genetic clones.
Past studies of behavioral differences in genetically identical cells have focused on genes that decide cell fate. However, Wood, Henne, and their colleagues took a different tact: They looked at the behaviour of different biomarkers associated with basic cell care, such as mobile cycling, stress response, intracellular communication, and nutrient signaling.
The researchers note that the role each of these factors plays in deciding cell fate is not yet clear. Learning more about the things that prompt cells to behave differently could eventually steer researchers in new directions. For example, the knowledge could be useful in helping cells respond to cancer chemotherapies or antibiotics, areas in which cells often take divergent paths.
How two identical cells side by side take different paths is a very basic biological question – we see it from bacteria to mammalian cells. Our results show that factors not traditionally associated with cell fate can, in fact, play an important role in this process, and gets us closer to answering the question of why this phenomenon takes place and how we might control it.”
N. Ezgi Wood, Ph.D., Postdoctoral Fellow at UTSW
To explore these questions, researchers genetically modified yeast cells so that five different protein markers associated with these maintenance tasks glowed with unique colors inside the cell when they were present. They then set up an experiment in which these cells lived in a microfluidics room that was continuously flushed with liquid media.
For two hours, this media was loaded with the nutrients which these cells required to multiply and survive, including sugar. Then, for the next 10 hours, the researchers cut off the glucose supply, starving the cells. At the end of this time, they reintroduced glucose, allowing the cells to recover. In this 16-hour cycle, a camera continuously monitored individual cells, looking for differences between those who became quiescent or senescent when glucose was available again.
When they reviewed the camera footage, researchers immediately saw that despite the cells growing in an asynchronized fashion, or at several points in their cell cycles, starvation ceased the cell cycle. A closer look showed that a protein inhibitor of the cell cycle known as Whi5 tended to accumulate in the nuclei of quiescent cells during starvation, whilst Whi5 in senescent cells disappeared altogether.
Likewise both populations exhibited differences in the proteins Msn2 and Rtg1 that are associated with stress response. Although these proteins gathered from the nuclei of all the cells when they were starved, they had a sustained presence in the nuclei of senescent cells even after sugar returned, yet largely exited the nuclei of quiescent cells when starvation ended.
The researchers found another useful marker for separating these two populations in the nucleus-vacuole intersection (NVJ), an interface that connects the nucleus to the vacuole, the tiny digestive organelle that cells use to sequester waste products. While quiescent cells tended to enlarge their NVJs during starvation, senescent cells did not.
Although all these findings gave clues to which path cells could take after starvation started, none showed any predictive powers before starvation happened. But when the researchers examined Rim15, a protein which plays a key role in nutrient signaling, they found that cells with elevated Rim15 before starvation tended to become quiescent while those with lower concentrations of the protein were more likely to become senescent.
On their own, none of these factors served as an accurate predictor of cell fate. However, when Wood, Henne, and their colleagues conducted a statistical analysis incorporating them all, they were able to accurately predict which cells became quiescent and which became senescent with an accuracy of nearly 90 percent until they reintroduced glucose. In fact, they say, cells seem to reach a”decision point” where it’s unlikely that they’ll change their direction about four hours to starvation.
UT Southwestern Medical Center
Wood, N.E., et al. (2020) Nutrient Signaling, Stress Response, and Inter-organelle Communication Are Non-canonical Determinants of Cell Fate. Cell Reports. doi.org/10.1016/j.celrep.2020.108446.