Why Reprogramming Makes Male and Female Cells Behave Differently

When male and female cells are converted into pluripotent stem cells, they start behaving differently. Molecular biologists from KU Leuven and UCLA show that these differences are linked to the number of X chromosomes in the original cells.

induced pluripotent stem cells
iPS cells obtained by reprogramming specialised cells show sex-specific differences in behaviour. These are due to the different number of X chromosomes © Vincent Pasque

Using a patient’s skin cells to restore his vision? Thanks to a promising technique known as cell reprogramming, this science fiction scenario may soon become reality.

The technique allows scientists to make stem cells from, for instance, a patient’s skin cells. These stem cells – known as induced pluripotent stem cells or iPS cells – can be turned into almost any specialised cell type of the human body, including the cells we need to see.

Working with iPS cells has numerous advantages compared with other methods. For one thing, you use adult cells to make iPS cells, so you no longer need embryos. Furthermore, the reprogrammed cells have the patient’s DNA, so the body will be less likely to reject them.

“Cell reprogramming is revolutionising medicine, yet surprisingly little is known about how it actually works,” says stem cell expert Vincent Pasque, assistant professor at KU Leuven, Belgium.

Cell reprogramming is revolutionising medicine, yet surprisingly little is known about how it actually works.

Together with Kathrin Plath from UCLA, Vincent Pasque from KU Leuven led an international study into how adult cells reprogram to iPS cells. To investigate the different stages of the reprogramming process, the researchers separated male and female cells to examine them side by side.

The team discovered that female and male cells behave differently after the reprogramming process and that this is due to their different number of X chromosomes – two in female cells and one in male cells.

Vincent Pasque explains: “In a normal situation, one of the two X chromosomes in female cells is inactive. But when these cells are reprogrammed into iPS cells, the inactive X becomes active. So the female iPS cells now have two active X chromosomes, while males have only one.”

“We now know that this explains the different behaviour of male and female cells after reprogramming because, over time, female cells lose one of the two X chromosomes and start behaving more or less like male iPS cells.”

The differences between male and female iPS cells are most pronounced for one of the key processes in the field of epigenetics: DNA methylation.

The differences between male and female iPS cells are most pronounced for one of the key processes in the field of epigenetics: DNA methylation, a modification that changes the activity of a DNA segment without changing its sequence. The researchers found that DNA methylations are erased in female iPS cells but not in male cells.

“Our study also indicates that the path towards iPS cells involves the use of specific control switches on DNA called enhancers,” adds Dr Constantinos Chronis from UCLA.

Vincent Pasque concludes: “Studying male and female cells separately is key to a better understanding of how iPS cells are made. And we really need to understand the process if we want to create better disease models and to help the millions of patients waiting for more effective treatments.”

induced pluripotent stem cells
Colonies of iPS cells under the microscope © Vincent Pasque
induced pluripotent stem cells
A colony of iPS cells obtained by reprogramming fibroblasts © Vincent Pasque

Source : KU Leuven