UC San Francisco researchers have for the first time developed a method to precisely control embryonic stem cell differentiation with beams of light, enabling them to be transformed into neurons in response to a precise external cue. The technique also revealed an internal timer within stem cells that lets them tune out extraneous biological noise but transform rapidly into mature cells when they detect a consistent, appropriate molecular signal, the authors report in a study published online August 26 in Cell Systems.

"We've discovered a basic mechanism the cell uses to decide whether to pay attention to a developmental cue or to ignore it," said co-senior author Matthew Thomson, PhD, a researcher in the department of Cellular and Molecular Pharmacology and the Center for Systems and Synthetic Biology at UCSF.

During embryonic development, stem cells perform an elaborately timed dance as they transform from their neutral, undifferentiated form to construct all the major organ systems of the body. Researchers have identified many different molecular cues that signal stem cells when to transform into their mature form, whether it be brain or liver or muscle, at just the right time. 

These discoveries have raised hopes that taking control of stem cells could let scientists repair damaged and aging tissues using the body's own potential for regeneration. But so far, getting stem cells to follow instructions en masse has proven far more difficult than researchers once expected.

In recent years, scientists have found that many of the genes encoding these developmental cues constantly flip on and off in undifferentiated stem cells. How the cells manage to ignore these noisy fluctuations but then respond quickly and decisively to authentic developmental cues has remained a mystery. 

"These cells receive so many varied inputs," said lead author Cameron Sokolik, a Thomson laboratory research assistant at the time of the study. "The question is how does the cell decide when to differentiate?" 

To test how stem cells interpret developmental cues as either crucial signals or mere noise, Thomson and colleagues engineered cultured mouse embryonic stem cells in which the researchers could use a pulse of blue light to switch on the Brn2 gene, a potent neural differentiation cue. By adjusting the strength and duration of the light pulses, the researchers could precisely control the Brn2 dosage and watch how the cells respond.

They discovered that if the Brn2 signal was strong enough and long enough, stem cells would quickly begin to transform into neurons. But if the signal was too weak or too brief, the cells ignored it completely.