For the first ten to twelve years, these studies were mainly focussed on embryonic development, therefore the formation of the pancreas where the beta cells are located. This part of the work was done by Marianne Voz. More recently, the laboratory has developed a regeneration model in the adult on which the study was done.
Pancreatic progenitors
![Pancreas Zebrafish]( "Pancreas Zebrafish.")
In an article which appeared in BMC Biology (1), the researchers provided a demonstration of pancreatic progenitors: these are not exactly stem cells (although the possibility has not been ruled out), they correspond to a slightly later stage in the differentiation of beta cells. Marianne Voz has identified these cells in the embryo: she showed that the cells that express nkx6.1, a gene coding for a transcription factor that is expressed very early in the embryonic pancreas, give rise to beta cells during embryogenesis.
Isabelle Manfroid and her team then looked at what happened in the adult: "We saw that the cells that expressed nkx6.1 are pancreatic duct cells and that they have the ability to form pancreatic beta cells that are in regeneration. For example, after selective destruction of beta cells in the zebrafish, the latter can regenerate them rapidly and spontaneously. We showed that the regenerated beta cells, or at least some of them, came from the cells that were expressing nkx6.1 in the pancreatic ducts".
By combining and comparing their information, Marianne Voz and Isabelle Manfroid realised that the nkx6.1 cells, both in the embryo and in the adult, express certain genes in common and have similar properties: these nkx6.1 cells can form beta cells at both of these stages of life. "Therefore, we find “embryonic” properties in the pancreatic duct cells in the adult: the latter explain a gene-battery present in the embryo which we know are necessary for the formation of beta cells. This was the first time that we were able to demonstrate this property", adds Isabelle Manfroid.
From the zebrafish to the mouse?
To carry out this work, the GIGA researchers created a tool which makes it possible to indelibly mark cells. "We made the progenitor cells fluorescent, and, based on this property, we were able to isolate them from the embryo or the adult and then analyse their transcriptome, that is to say, we were able to see which factors and which genes they express, over time or in different conditions, like regeneration. Thanks to this very powerful tool, we can mark cells, monitor them and see what happens at a molecular level. It is a real breakthrough", says a delighted Marianne Voz.
Now that these progenitor cells have been demonstrated, how do the two researchers plan to continue their work? “In the case of the adult, as far as I am concerned”, says Isabelle Manfroid, “0nce we have identified the cells that enable regeneration and make it possible to create new beta cells, we then need to understand why and how. Once we have understood these mechanisms, or at least some of them, we will be able to use mice (a model in which it is also possible to perform beta cell ablation) to see whether we can stimulate these mechanisms by using pharmacological compounds, for example. Over the next five years, the main task will be to really elucidate these mechanisms, the transition to using mice as a model could take up to five or six years. Demonstrating that it is possible to transpose the procedure to mammals is a key point”.
"For us, explains Marianne Voz, “what is important is to understand what role this nkx6.1 factor plays in the ducts in the embryo. Understanding how it works in terms of the development of the organism”.
