Erasing epigenetic 'memory' to improve the quality of stem cells

It’s been 16 years since scientists first coaxed skin cells back into their embryonic state, a development that made it possible to sidestep the thorny ethical dilemmas around sourcing human stem cells from fetal tissue to produce them en masse. But progress in regenerative medicine has been hampered by the fact that while the resulting induced pluripotent stem cells, or iPS cells, are very similar to natural stem cells, their genomes still carry the biological “memories” of the cells from which they were derived.

Now, a research team led by scientists from Australia’s Harry Perkins Institute of Medical Research, the University of Western Australia, Monash University and the University of Adelaide have found a way to make the transformation more thorough, expanding their use in the lab and, potentially, in the clinic. In a study published Aug. 16 in Nature, the researchers described how they developed a method that resets a cells’ genes so they look just as they did in the earliest stages of embryonic development.

“This significantly reduces the differences between iPS cells and [embryonic stem cells] and maximizes the effectiveness of how human iPS cells can be applied,” study co-lead Jose Polo, Ph.D., an epigeneticist at Monash, said in a press release.

Before they could figure out how to make iPS cells look more like natural stem cells, the researchers first needed to address some knowledge gaps about exactly what happens to somatic cells as they revert back to their embryonic state. To do that, they performed a technique called genomewide DNA methylation profiling on somatic, or body, cells as they transformed into stem cells. This showed the trajectory of epigenetic changes, which don’t actually change the DNA but how the genes are expressed.

Running the same profiling technique on natural embryonic stem cells showed the scientists the differences between the two; iPS cells had many more epigenetic changes than embryonic stem cells. Armed with these data, the scientists devised a method called transient-naive-treatment, or TNT, which stabilizes the somatic cells as they transform by adding a step that resets the genome to that of an embryonic stem cell.

When the researchers checked how well the method worked, they found that using TNT had reset the iPS cells’ genomes to the degree that about 71% of the differences between them and natural embryonic stem cells was extinguished. Cells that underwent the conventional method of correcting aberrations between iPS and embryonic stem cells, somatic cell nuclear transfer reprogramming, had a success rate of about 60%.

“[This indicates] … that TNT reprogramming is more effective at epigenetic correction,” the researchers wrote in their paper.

To see whether the new method improved the quality of cells differentiated from iPS cells, the researchers reprogrammed TNT iPS cells into neurons, skeletal muscle cells, lung epithelial cells and neural stem cells. They saw that the treated stem cells consistently differentiated more efficiently than untreated stem cells, regardless of what type of cell they were before being transformed.

“We foresee TNT reprogramming becoming a new standard for biomedical and therapeutic applications and providing a novel system for studying epigenetic memory,” the researchers wrote.