Stem cells: you’ll be what you must be

Stem cells play a key role in the development and preservation of life as they are in charge of their own renewal/redevelopment –keeping a sort of stem cells’ repository- and distinction from different types of special cells that form an individual, such as the muscular, the epithelial or neuronal ones, among others. The dynamic balance between renewal and distinction has to be accurate so as not to generate one proliferative disease such as cancer or the loss of the organs’ functionality. In order to understand which factors are involved in the stem cells’ fate determination, an international group or researchers that included one CONICET La Plata scientist conducted a study that was recently published in Development.

“The complete functioning of stem cells is still unknown”, states Nara Guisoni, CONICET associate researcher at the Instituto de Física de Líquidos y Sistemas Biológicos (IFLYSIB, CONICET – UNLP) and author of the study. “Not so long ago experts believed that these cells were divided into two: one that keeps its identity, and the other one that is differentiated. According to this paradigm, stem cells would be eternal as their cell lineage would continue indefinitely. Now we know that it’s not always like that. In some situations, two equal cells are created, and the cell fate determination depends on the interaction among them and the environment. We still don’t know which are the mechanisms involved in that decision and what factors are important in the process.”

In 2010, due to an external fellowship for young researchers at CONICET, the scientist joined the Systems Biology group led by Jordi García Ojalvo of the Universidad Pompeu Fabra in Barcelona, Spain. So she began to study the subject considering Drosophila melanogaster intestine as a model, the most commonly fruit fly, whose organism has some similarities with others that are more complex, like the mammals’.

“Lateral inhibition is a very general mechanism for the cell fate that is present in the D. melanogaster intestine, where two neighboring cells mutually block the production of a determined protein. So, a competence starts in which a small asymmetry in the concentration of that protein is increased and that defines which one remains a stem cell and which is differentiated. For this reason, two ‘equal’ cells with the same fate turn into two different ones with distinct fates”, Guisoni describes.

“The problem we had was that that lateral inhibition mechanism was not enough to explain experimental data that accounted for the fact that in the D. melanogaster intestine there were pairs of cells with different fates like with one same fate, like the two stem cells or both differentiated ones. There had to be something to generate more fate diversity, beyond that dispute that was thought to be solved considering that each cell had one distinct pathway”, Guisoni comments.

“We conducted different theoretical tests based on one mathematical model for lateral inhibition, so we proposed that the key could be in the sensitivity of one cell to another neighboring one. The proteins that intervene in the mutual inhibition process are present in the cell membranes. So possibly the variability in the contact area among the non differentiated cells was a factor that can regulate the fate determination of the cells”, the scientist states.

In order to assess that hypothesis, the scientists analyzed tridimensional images of the D. melanogaster intestine cells and could measure the contact area. They also managed to prove that there was variability and the intensity of that intereaction was related to the type of fate each of them has. “With little contact, the mutual inhibition cell is weak so the cells do not diffentiate; and in the opposite case, they both probably do it. We showed that the geometry of the cells, that is to say the shape in which they are compacted, exerts influence on the determination of their fates. Therefore, in order to maintain the balance in the stem cells and the differentiated cells, apart from the signaling by different molecules, the shape in which they are grouped is also an important ingredient”, the researcher said.

To conclude, Guisoni stresses “what we managed to obtain was the result of a multidisciplinary study between physicists and biologists, in which each one contributed and we all worked on mathematical and experimental models. Although we are devoted to basic research, the knowledge on stem cells is vital for future technological applications related to health.”