Researchers from the University of California in San Francisco have discovered how to differentiate embryonic stem cells (ESCs) with light. Irradiation with beams of light transformed ESCs into neurons. The research team lead by Matt Thomson also found out how cells distinguish meaningful developmental signals from stochastic molecular fluctuations. The study was published in the journal Cell Systems.
The embryonic development transforms undifferentiated cells into specialized forms that will build all the organs in the organism. Many of the molecular signals that intervene in that process of maturation have already been identified.
A complete knowledge of all the molecular instructions that happen in ESCs differentiation and the right timing for those cues would allow scientists to have a complete control of ESCs to repair and construct tissues. Unfortunately, most of the genes that have a role during cell differentiation are constantly being switched on and off in ESCs, and many of those changes are just biological noise. Scientists do not know how cells distinguish background noise from the real developmental cues.
Matt Thomson and his team conducted experiments to test how ESCs identify real developmental signals and dismiss noise. Brn2, when expressed, triggers neural differentiation. The researchers engineered the Brn2 gene so that it was expressed when cells received a pulse of blue light. They were surprised to see that Brn2 expression levels could be controlled by changing the pulse intensity and duration.
Low levels of Brn2 are interpreted as stochastic molecular fluctuations
Co-senior author Stanley Qi and co-author Yanxia Liu tagged Nanog, an anti-differentiation transcription factor, with a flourescent protein to track it during Brn2 expression. They found out that Brn2 acts as a differentiation factor -by disrupting a molecular mechanism that keeps cells undifferentiated- only over a certain light intensity and duration. When Brn2 levels increase, the anti-differentiation mechanism is disrupted by evicting Nanog, whose levels slowly drop. But if Brn2 expression is just of stochastic origin, Nanog quickly reestablishes the mechanism, as it takes 4 hours to deplete it.
Dr. Thomson thinks that this mechanism might be also found in other differentiation processes. He plans to use the light-inducible differentiation to study complex tissue formation in 3D. In the future, he envisions the possibility of irradiating a cell culture with lights of different color, each one triggering a different developmental mechanism, eventually resulting in a complex organ that could be transplanted.