Two distinct types of reprogramming
Stem cells generated with Oct4 cannot form a complete organism
Somatic cells have already assumed specific tasks through differentiation, but they can be reprogrammed into “all rounders”: by using only four factors, a specialised somatic cell can thus regain its ability to form any type of cell (pluripotency). One of those factors is Oct4. Scientists from Hans Schöler’s team at the Max Planck Institute for Molecular Biomedicine in Münster have now been able to demonstrate that an egg cell does not require Oct4 to develop into a complete organism (totipotency). This means that reprogramming cells to make them pluripotent by using the four factors, including Oct4, and reprogramming an egg cell through fertilisation or cloning are significantly different processes.
For quite some time, scientists have ascribed Oct4 an important role in early embryonic development—after all, the protein is present in the egg cell. To study the role of Oct4 in the transition from totipotency to pluripotency, the Max Planck researchers had to deactivate Oct4 in the egg cell. To do this, they used a genetically modified mouse model in which the protein Oct4 was eliminated only in the egg cells. “Contrary to the established premise that Oct4 is crucial for the early embryonic stages of development, the mice without Oct4 were as fertile as those with Oct4,” according to Guangming Wu, first author of the study. “In other words, it was still possible to activate the totipotency of the fertilised egg cells, as in normal fertilisation,” he adds.
Another established assumption was that the fate of the cells in the early embryo is decided by the balance between the protein Oct4 and its antagonist, the protein Cdx2. According to this assumption, Oct4 would turn the cells into embryoblast cells, from which the foetus would later form. Cdx2, on the other hand, would transform the cells into trophoblasts, a subsequent part of the placenta. Consequently, without Oct4, there would be an empty trophoblast envelope. The researchers found that despite the elimination of Oct4, an embryo with an embryoblast formed. However, the cells quickly lost their pluripotency. Wu explains, “There must therefore be other factors that determine the fate of the cells in the early embryo. Identifying the factors that are decisive for embryonic cloning and pluripotency will be the subject of future research.”
In 2009, Hans Schöler and his team demonstrated that certain somatic cells could be reprogrammed into stem cells by using Oct4 alone. Scientists hope that they will be able to use such induced pluripotent stem cells to better study diseases without requiring human embryos to harvest stem cells. “Our study shows that cloning leads to totipotency with or without Oct4, while reprogramming cells for pluripotency is not possible without Oct4,” Hans Schöler explains. “The two types of reprogramming are fundamentally different. This is also an important finding with regard to the Embryo Protection Act. If these two processes were to involve the same mechanisms, there could be totipotent cells among the induced pluripotent stem cells generated with Oct4, in which case the Embryo Protection Act would apply.”