Embryonic stem cells are classified as pluripotent cells because they are able (“potent”) to mature into almost every (“pluri”) cell type. Thanks to Nobel Prize winner Shinya Yamanaka, researchers have been able to reprogram fully matured cells, like skin or blood, into embryonic stem cell-like induced pluripotent stem cells (iPS). The technique has revolutionized stem cell science, providing human models of disease and the prospect of personalized cell therapies.
And yet it has remained unknown if reprogramming cells resembling so-called totipotent cells is possible. Unlike iPS or embryonic stem cells, totipotent cells have complete shape-shifting abilities in that they can give rise to all (“toti”) the cell types of the developing embryo including the placenta and umbilical cord. They appear briefly during the earliest stages of development when the fertilized embryo is made up of just one or a few cells. Could lab-derived totipotent cells provide an equally or even more powerful research tool than iPS cells?
The stem cell field is now in position to ask that question. This week scientists from French Institute of Health and Medical Research (INSERM) and the Max Planck Institute in Germany report in Nature Structural Biology that they successfully induced mouse embryonic stem cells to take on totipotent characteristics.
To achieve this feat, the scientists started with the known observation that a small amount of totipotent cells spontaneously appear when growing pluripotent stem cells in petri dishes. They are called 2C-like cells because of their likeness to the cells of the two-cell embryo. The team isolated those 2C cells and carefully compared them to the pluripotent embryonic stem cells. They noticed the DNA in 2C cells had a looser structure, which indicates more flexibility to switch on many different genes in a cell. With this information, they found that a protein called CAF1 known to play a role in making a tighter DNA structure, and inhibiting genes, was reduced in the totipotent 2C cells.
By experimentally blocking the function of CAF1 in pluripotent cells, the tightened DNA structure was loosened, leading to more genes being switched on and inducing a totipotent state. With these cells in hand, the team can now examine their possible impact on accelerating progress in regenerative medicine. Maria-Elena Torres-Padilla, the lead scientist on the project, pointed out in a press release the significance of these cells for future studies:
“Totipotency is a much more flexible state than the pluripotent state and its potential applications are extraordinary.”