How to reprogram a cell into a stem cell? Wipe its memory

Australian researchers have developed a new method to reprogram human cells to better mimic embryonic stem cells called transient-naive-treatment (TNT).
Sejal Sharma
Human iPS cells
Human iPS cells

Monash University 

Stem cells, serving as a repair system for our body, generate all other cells with specialized functions. There are two main types of stem cells: embryonic stem cells and adult stem cells.

In a scientific advancement in the 2000s, it was discovered that somatic cells, which are responsible for the growth and development of an organism, could be artificially reprogrammed into a state that resembles embryonic stem (ES) cells, also known as induced pluripotent stem (iPS) cells. These cells can then generate any cell in the body.

And now, a team of Australian researchers has developed a new method to reprogram human cells to better mimic ES cells, with significant implications for biomedical and therapeutic uses, as per a press release from Monash University.

A way to wipe a cell’s memory

That the researchers were able to artificially reprogram somatic cells into iPS means that we can have an unlimited supply of these cells which can be used in regenerative medicine.

“However, a persistent problem with the conventional reprogramming process is that iPS cells can retain an epigenetic memory of their original somatic state, as well as other epigenetic abnormalities,” said Professor Lister, co-author of the paper. “This can create functional differences between the iPS cells and the ES cells they’re supposed to imitate, and specialized cells subsequently derived from them, which limits their use.”

Reprogramming a cell as a stem cell

iPS cells can bear a memory of their previous history. To erase this epigenetic memory, the team developed a new method called transient-naive-treatment (TNT). The TNT mimics the properties of the way a cell was during its very early embryonic development.

“This significantly reduces the differences between iPS cells and ES cells and maximizes the effectiveness of how human iPS cells can be applied,” said Professor Jose Polo, another co-author of the study.

Co-first author of the study, Jia Tan, said that the team’s TNT method was dynamite. “It solves problems associated with conventionally generated iPS cells that if not addressed could have severely detrimental consequences for cell therapies in the long run."

The researchers concluded in their study that they foresee TNT reprogramming becoming a new standard for biomedical and therapeutic applications and providing a novel system for studying epigenetic memory.

The study was published in the journal Nature.

Study abstract:

Cells undergo a major epigenome reconfiguration when reprogrammed to human induced pluripotent stem cells (hiPS cells). However, the epigenomes of hiPS cells and human embryonic stem (hES) cells differ significantly, which affects hiPS cell function. These differences include epigenetic memory and aberrations that emerge during reprogramming, for which the mechanisms remain unknown. Here we characterized the persistence and emergence of these epigenetic differences by performing genome-wide DNA methylation profiling throughout primed and naive reprogramming of human somatic cells to hiPS cells. We found that reprogramming-induced epigenetic aberrations emerge midway through primed reprogramming, whereas DNA demethylation begins early in naive reprogramming. Using this knowledge, we developed a transient-naive-treatment (TNT) reprogramming strategy that emulates the embryonic epigenetic reset. We show that the epigenetic memory in hiPS cells is concentrated in cell of origin-dependent repressive chromatin marked by H3K9me3, lamin-B1 and aberrant CpH methylation. TNT reprogramming reconfigures these domains to a hES cell-like state and does not disrupt genomic imprinting. Using an isogenic system, we demonstrate that TNT reprogramming can correct the transposable element overexpression and differential gene expression seen in conventional hiPS cells, and that TNT-reprogrammed hiPS and hES cells show similar differentiation efficiencies. Moreover, TNT reprogramming enhances the differentiation of hiPS cells derived from multiple cell types. Thus, TNT reprogramming corrects epigenetic memory and aberrations, producing hiPS cells that are molecularly and functionally more similar to hES cells than conventional hiPS cells. We foresee TNT reprogramming becoming a new standard for biomedical and therapeutic applications and providing a novel system for studying epigenetic memory.

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