What Makes Stem Cells Transform? A Persistent Signal

A brain-like network of neural progenitors 96 hours after being stimulated to turn into neurons. Image courtesy of Thomson lab/UCSF

In new work at UCSF, researchers were able to control embryonic stem cell differentiation by light stimulation, after genetically engineering the cells to be light responsive. In the process, the research also revealed that stem cells possess a timer system, which can 'tune out' biological noise, or trigger transformation if an external signal remains persistent. 



“We’ve discovered a basic mechanism the cell uses to decide whether to pay attention to a developmental cue or to ignore it”





Embryonic cell differentiation is tightly controlled and timed: following a careful, orchestrated pattern which gives rise to a foetus. As interest in stem cells has grown, more research has been conducted around exactly what triggers control differentiation into specific tissue. 

We already know that various developmental genes flip on and off constantly in embryonic stem cells, but researchers wanted to discover exactly how cells cut through this noise - decisively acting when a 'real' signal emerges. In order to analyse this process, a gene called Brn2 was altered to become light responsive: Brn2 is a known neural differentiation cue that triggers neuron growth. By modulating light strength, the researchers could change the expression of the gene, producing a strong or weak signal. What they found was that the cells only responded when the signal was both strong and continued for a long time.

Uncovering how stem cells decide to differentiate is essential for progress in regenerative medicine



“The cells are looking at the length of the signal”





After further observation, the team found that a persistent signal had a direct effect on another protein called Nanog, which acts as a sort of gatekeeper protein. When a persistent signal lowered this protein enough after a number of hours - it opened the gates towards transformation. If this Nanog protein is depleted and there is a signal like Brn2 present, the cell springs into action and differentiates into a particular cell. 


“There’s lots of promise that we can do these miraculous things like tissue repair or even growing new organs, but in practice, manipulating stem cells has been notoriously noisy, inefficient, and difficult to control. I think it's because the cell is not a puppet. It’s an agent that is constantly interpreting information, like a brain. If we want to precisely manipulate cell fate, we have to understand the information-processing mechanisms in the cell that control how it responds to the things we're trying to do to it.”

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