Next Level with Super-Sox

An article from carl 03|2025

by Karin Hollricher

A team of researchers improved the cooperation between two transcription factors to such an extent that induced pluripotent stem cells, in particularly high quality, can now be produced. This opens up new directions for research, for the development of treatments and even for the preservation of endangered animal species.

Almost 20 years ago, Japanese researchers discovered that, with the help of the four transcription factors Oct4, Sox2, Klf4 and Myc, differentiated mice cells can be returned to a state similar to stem cells [1]. This molecular mixture – called a Yamanaka cocktail after the Japanese researcher Shinya Yamanaka – has since been used in a modified form for the production of induced pluripotent stem cells. Using these iPS cells (iPSCs), different cell types, such as nerve cells or myocardial cells, can be produced. Although much improved, the procedure is not very efficient, especially with human cells: the quality and quantity of the iPSCs fluctuate greatly – some iPS cell lines can be differentiated to any kind of body cell while others fail completely. 

Oct4 is a problem. This molecule is like a wild dog, says Hans Schöler from the Max Planck Institute (MPI) for Molecular Biomedicine in Münster [2]. It single-handedly activates genes that prevent cells from becoming pluripotent. So, the search began for a way to keep Oct4 “on a short lead”. Researchers from several universities and institutions, including the MPI in Münster, were successful. They developed the super-SOX molecule, which drastically improves the quality of iPS cells [3]. 

How super-SOX works

The duo comprising the two components Oct4 and Sox2 is the master regulator that is indispensable for the production of iPS cells. Both molecules do also bond individually with DNA, but in order for pluripotent stem cells to be obtained again from differentiated body cells, the two molecules must cooperate. Only together, as a heterodimer, can they transfer the chromatin of differentiated cells into a quasi embryonic state, in which previously silenced genes are reactivated. The cooperation between the two molecules is established via contacts between their DNA binding domains [2] (see figure). Sox2 forms a weaker bond with Oct4 than the very similar Sox17, but this in turn cannot make cells pluripotent. It was found that just one amino acid was responsible for the stronger bond between Sox17 and Oct4: the one at position 61. If you replace the alanine at this position in Sox2 with a valine, i.e. place the amino acid from Sox17 there, you get a strongly binding and highly efficient factor – the super-SOX molecule [3].

This super-SOX actually keeps Oct4 “on a short lead” by forming a stronger bond with Oct4 and thus preventing Oct4 from activating the genes that disrupt the reprogramming. At the same time, super-SOX, unlike Sox2, has the ability to generate pluripotency. This not only works in the cells of mice and humans, but also in the cells of pigs, cows and macaques. The key role of the Sox2-/Oct4-dimer in pluripotency appears to be conserved in all mammals, according to stem cell researcher Sergiy Velychko, senior author of the study. Through rational engineering and targeted evolution, it may be possible to develop even more efficient reprogramming factors, the researchers concluded in their report [3].

New options

The improved transformation efficiency of differentiated body cells into pluripotent stem cells will not only facilitate clinical applications, but will also enable the acquisition of iPS cells from endangered animal species. Such cells could, for example, be stored as a “stem cell Noah’s ark” and used to preserve species. In a press release from the MPI, Schöler explains that “many questions are still unanswered in this connection, and good interdisciplinary collaboration is required to be able to effectively and safely transfer the possibilities created through this work into practice.” [2] 

[1] K. Takahashi und S. Yamanaka, 2006, Cell 126, 633-676
[2] www.mpi-muenster.mpg.de/pressemitteilung/super-sox 
[3] C. MacCarthy et al., 2024, Cell Stem Cell 31, 127-147

Image credits: © Vlad Cojocaru, Max-Planck-Institut für molekulare Biomedizin