Stem Cells’ Existential Crisis Explained

Either/or molecular circuitry modeled

To differentiate or not to differentiate? That is the question constantly faced by embryonic stem cells. And they seem to answer it decisively at the behest of a molecular trio of transcription factors. A new computational model shows how it is possible for three proteins to control the switch in the observed, clear-cut manner. The model also gives researchers a hypothesis they can test in the lab.


“We’ve shown that these three players are able to define the embryonic stem cell switch,” says Carsten Peterson, PhD, professor of computational biology at Lund University in Sweden and lead author of the study. By explaining this either/or molecular circuitry, the model could eventually help scientists harness stem cells for treatments. The work appears in the September 2006 issue of PLoS Computational Biology.


Embryonic stem cells have two defining traits: They can divide forever to remain stem cells, and they are pluripotent, meaning they have the potential to become any type of somatic cell in the body—gut, muscle, skin, blood or nerve. But whether in a Petri dish or the body, stem cells receive a barrage of molecular signals that they must interpret and respond to with a binary decision. “Either you are a stem cell or you commit yourself,” says Peterson.


A+ represents hypothetical factors that activate OCT4 and SOX2. In response to increasing that signal, the OCT4-SOX2 dimer and NANOG switch from all off to all on. B- represents factors that repress NANOG, which has the effect of turning the switch off. Courtesy of Carsten Peterson.Over the last few years, biologists have discovered that a handful of proteins determine an embryonic stem cell’s fate. Three in particular—named OCT4, SOX2 and NANOG—seem to coordinate the decision by cueing the actions of hundreds of target genes.


Peterson’s team derived mathematical equations governing the rate at which these three transcription factors bind and unbind to DNA, thereby regulating the expression of differentiation genes and stem cell genes. The team then used the Systems Biology Workbench to simulate how this trio controls other genes to engineer opposing outcomes: self-renewal or differentiation. They infer that the proteins reinforce one another’s actions through a positive feedback mechanism, creating a bistable switch: either on or off, with no middle ground. When all three proteins are active, stems cells remain stem cells; when the trio is inactive, the cells differentiate, with no middle ground. Peterson and others hypothesize that stem cells receive external signals to control the switch. Because of the positive cascade of interactions, the cells effectively ignore slight changes in those signals and respond with a single outcome every time.


The model was based on previous work by Laurie Boyer, PhD, a postdoctoral fellow at the Whitehead Institute in Cambridge, Massachusetts. She thinks other components must function with the trio of proteins. However, she says, the work “provides a testable model to explain how OCT4, SOX2 and NANOG may contribute to these seemingly opposing activities.”


The heart of the model—explaining how stem cells reconcile their dual identities—is vital, says Boyer. “If you are ever going to realize the therapeutic potential of these cells, you really need to find the key for understanding how embryonic stem cells balance their ability to self-renew or differentiate.”



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