Australian-based scientists have developed a new method for wiping the epigenetic memory of human cells when they undergo re-programming to become stem cells.
The breakthrough, published in Nature, overcomes a persistent problem with using re-programmed human cells, called induced pluripotent stem (iPS) cells.
Since the mid-2000s scientists have been able to create iPS cells – taking cells from one part of the human body, such as skin or blood cells – and re-programming them.
The iPS cells provide an alternative to using embryonic stem cells. This is significant given the ethical and legal considerations associated with cells derived from a human day-6 embryo.
University of Monash Professor Jose Polo says iPS cells are very similar to embryonic stem cells, “they have the capacity to differentiate very easily into any cell of the body”.
For example, Polo says, the iPS cells can be used to make neurons to study neural degenerative diseases, or to make cardiac cells. They can also be used in personalised therapies.
However, co-author Professor Ryan Lister from the Harry Perkins Institute of Medical Research says, “a persistent problem with the conventional re-programming process is that iPS cells can retain an epigenetic memory of their original somatic state, as well as other epigenetic abnormalities.”
He says this problem can create functional differences between the iPS cells and the embryonic stem cells they’re supposed to imitate, which limits their potential uses for disease modelling, drug screening and cell based therapies.
The new research solves this problem via a new method, called transient-naïve-treatment (TNT) re-programming. It’s a step which effectively wipes the epigenetic memory of the iPS during the re-programming process.
The result is iPS cells that more closely resemble embryonic stem cells.
The solution draws inspiration from what happens in nature.
“What we’ve done in the end is mimicking to some degree what happens during early human embryonic development,” Lister says.
“So, in the human embryo, prior to implantation in the uterine wall, there’s a period where the parental genomes that came from the sperm and egg are reset in these early cells of the embryo. And many of these epigenetic marks are removed, and you get this wave of removal of the epigenetic marks, and then re-addition of them.”
Lister emphasises, “we’re using findings from fundamental science that have revealed natural processes of how the epigenome resets”.
Polo says in embryonic stem cells very early in development, before day 5, the cell undergoes a full ‘clean-up’ of the epigenome.
He says “evolution realised at some point this was good, because otherwise you were carrying epigenetic aberrations of your parents.”
The benefits of the TNT re-programming, Lister says, are that the target cells created from iPS cells are a more accurate reflection of the real human equivalent cells in the body, and the step makes the re-programming process more efficient.
Finally, TNT re-programming is very straightforward to implement for other researchers, he says. “We hope it’s taken up probably by the research and biotech and cell therapy communities to utilise.”
The published research demonstrates the TNT re-programming in skin cells.
Next, the team plans to tailor and translate the protocol using blood cells. They also hope to better understand why the epigenetic memory is retained in iPS cells in the first place.
Lister says, “we predict that TNT reprogramming will establish a new benchmark for cell therapies and biomedical research, and substantially advance their progress.”
