‘Safe Driving Course’ For stem cells

Esrrb gene drives the differentiation of pluripotent stem cells. This discovery stemmed from the collaboration of two Armenise Harvard CDA awardees, Graziano Martello from the University of Padua and Davide Cacchiarelli from Tigem.

«Power is nothing without control». This famous, old-fashioned advertisement could be used to explain new research led by Graziano Martello of the University of Padua and an Armenise Harvard Career Development Award winner. The study, published in Nature Cell Biology, demonstrates the critical role that the Esrrb gene plays in the differentiation of stem cells. The research was coordinated by the University of Padua and realized in collaboration with Tigem in Pozzuoli and the European Molecular Biology Laboratory (Embl) in Rome. It was funded by the Giovanni Armenise Foundation and the Telethon Foundation.

Capable of creating any cell or tissue, pluripotent stem cells are widely used in laboratories dealing with regenerative medicine. Pluripotent stem cells are much like those formed during embryonic development and can give life to heart, intestine, or brain cells.

For some years, scientists have hypothesized that a specific mechanism guides the differentiation of pluripotent cells. Until now, however, it hasn’t been possible to confirm this hypothesis, or find the gene responsible for this mechanism.

As part of the Armenise-Harvard Pluripotent Stem Cell Laboratory at the University of Padua and first author of the work, Elena Carbognin explains: «We began by questioning what happens during the initial phase of differentiation. Eager to understand how stem cells prepare for differentiation, we witnessed that changes took place every two days. This means that in two days, a change occurs that gives the cell the ability to differentiate, and as the metabolism changes, the organization of the DNA changes. However, what could control this change? We found that the Esrrb gene guides pluripotent cells through the initial phases of differentiation. In fact, when we remove this gene, pluripotent stem cells differentiate out of control».

Pluripotent stem cells can give rise to any type of cell, including sperm and oocytes (a female germ cell) that are involved during reproduction and give rise to a new organism following fertilization.

«We observed that in the absence of Esrrb it is no longer possible to obtain germ cells», says Jamie Hackett, a scientist at EMBL in Rome and co-author of the study.

«It was fascinating to observe how pluripotent cells rapidly modify their DNA, in preparation for their differentiation. We were able to study these mechanisms thanks to the state-of-the-art genomics techniques available at the Telethon Institute of Genetics and Medicine (Tigem), of which I am a member», comments Davide Cacchiarelli, co-author and head of the Armenise-Harvard Laboratory of Integrative Genomics at Tigem. Both Davide Cacchiarelli and Graziano Martello, who led this research, won the Armenise Harvard Career Development Award, respectively in 2017 and 2014.

Graziano Martello, from the Department of Biology of the University of Padua and group leader of the Armenise-Harvard Pluripotent Stem Cell Laboratory, states: «For researchers, this discovery is like a safe driving course that can identify how and what makes the car steer to the right or left. Knowing that a specific gene can drive such a course is quite exciting, and now we know how the fundamental step in cellular differentiation works. The prospects of this knowledge for research, not only basic but also clinical, is like shedding a new light».