Pluripotent stem cells (PSCs) have the capacity to give rise to all cells of our body, such as neurons or cells of our skin or blood. They also expand easily in our laboratories and it is possible, via a process named “reprogramming”, to make personalised PSCs.
From a small skin biopsy or a blood sample of a patient, affected, for instance, by a neurodegenerative disease, it is now possible to obtain PSCs and to differentiate them into neurons that will display defects found also in the patient. In other words, PSCs give the unprecedented possibility to study human diseases and test drugs in a dish.
For all these reasons, PSCs have the potential to revolutionise modern medicine.
However, our understanding of the behaviours of human PSCs is partial, we need to better understand how they differentiate, in order to make the process more efficient.
For example, in some cases, the neurons obtained are not fully matured as those found in the adult brain.
The process of reprogramming could also be optimised, both in terms of efficiency and costs and in terms of obtaining PSCs of better quality.
Metabolism is defined as a large set of chemical reactions that maintain a cell alive, or an entire organism, by providing energy, by providing the “building blocks” of the cell and by eliminating the waste products.
Metabolism has been for a long time considered as a static component of cellular physiology, a sort of “cellular housekeeping”. However, we increasingly appreciate how metabolism has the capacity to dynamically affect the behaviour of the cell.
Thus, our overall objectives have been understanding the role of metabolism in the process of PSC differentiation and in reprogramming, in order to make these processes more efficient.
In the context of PSC differentiation, we started from the observation that inactivation of some metabolic pathways affected the rate of differentiation. We then identified specific metabolites, whose levels control the differentiation process, making it faster or slower. We also investigated the molecular mechanism by which these metabolites act, which is by making some portions of the genome more or less active.
We also investigated the process of reprogramming, starting from the observation that a mild inhibition of energy production was enough to completely block the generation of PSCs. We have been able to significantly increase reprogramming efficiency, by using computational tools, which allowed us to simulate reprogramming under several different conditions and then perform real experiments only under the most promising conditions. We further optimised reprogramming by miniaturising the process, increasing the efficiency while reducing the amount of reagents needed.
Finally, we demonstrated that the mechanisms we are studying in PSCs are also relevant for other stem cells. The stem cells that constantly renew our intestine are under the same metabolic control we identified in PSCs, further demonstrating how metabolism has the potential to control key aspects of our physiology.
