Babraham Institute researchers turn the clock back on human skin cells by 30 years
Astonishing research from the Babraham Institute has succeeded in turning back the clock on human skin cells by 30 years, opening the door to a revolution in regenerative medicine.
The researchers were able to restore youthful function to the old cells - findings that could ultimately lead to targeted approaches to treat age-related problems.
Building on Nobel Prize-winning technology on cellular reprogramming, the work hints at the possibility that in future we could create cells that are better at healing wounds.
Dr Diljeet Gill, a postdoc in Prof Wolf Reik’s lab at the Babraham Institute, who conducted the work as a PhD student: “Our understanding of ageing on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells.
“We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved.”
Our cells’ ability to function is known to decline with age, with the genome accumulating marks of ageing.
The field of regenerative biology explores the repair or replacement of cells, including older ones, and deploys technology to create induced stem cells through a series of steps that erases some of the market that give cells their specialisms.
Shinya Yamanaka was the first scientist who showed that normal cells with a specific function could be turned into stem cells with the special ability to develop into any cell type.
He shared the 2012 Nobel Prize in Physiology or Medicine with Cambridge biologist Sir John B Gurdon for the finding.
The process of stem cell reprogramming, using four key molecules called the Yamanaka factors, takes 50 days and is used today to help create cells for research. In theory, the stems cells can be turned into any type, but it has proved difficult to reliably recreate the conditions to differentiate stem cells into certain cell types.
The work at Babraham, called ‘maturation phase transient reprogramming’, exposes cells to Yamanaka factors for just 13 days.
This, they have found, means not all of the cells’ identity is erased because the reprogramming is halted. This approach, they say, achieves a precise balance between reprogramming cells, which makes them biologically younger, while still enabling them to regain their specialised cell function.
They found that age-related changes were removed by this stage and the cells had temporarily lost their identity. But given time to grow under normal conditions, these partly-reprogrammed cells were able to regain their specific skin cell function.
The researchers used genome analysis to show that markers characteristic of skin cells, or fibroblasts, had been regained and they confirmed the finding by observing collagen production in the reprogrammed cells.
Collagen is found in bones, skin tendons and ligaments and helps to provide structure to tissues and heal wounds.
The researchers found the rejuvenated fibroblasts produced more collagen proteins compared to control cells that did not undergo the reprogramming process.
In our bodies, fibroblasts also move into areas that need repairing.
To test the partially rejuvenated cells, researchers created an artificial cut in a layer of cells in a dish.
The treated fibroblasts moved into the gap faster than older cells, which they say is a promising sign that in may in future be possible to create cells that are better at healing wounds.
While the work is still at an early stage, the researchers hope it will open other therapeutic possibilities too.
Their method also had an effect on other genes linked to age-related diseases and symptoms.
They found the APBA2 gene, which is associated with Alzheimer’s disease, and the MAF gene, which plays a role in the development of cataracts, both showed changes towards youthful levels of transcription.
Diljeet said: “Our results represent a big step forward in our understanding of cell reprogramming. We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of ageing indicators in genes associated with diseases is particularly promising for the future of this work.”
Cellular ageing can be assessed through the epigenetic clock, in which chemical tags present throughout the genome indicate age. A second measure is the transcriptome, which is the gene readouts produced by a cell.
Taking these two measures together, the Babraham researchers say the reprogrammed cells match the profile of cells some 30 years younger compared to reference data sets.
But the mechanism behind this successful transient reprogramming is not yet fully understood and must be explored further.
The researchers, who have published their work in eLife, have speculated that key areas of the genome involved in shaping cell identity might escape the reprogramming process using this method.
Professor Wolf Reik, a group leader in the epigenetics research programme at the Institute, said: “This work has very exciting implications. Eventually, we may be able to identify genes that rejuvenate without reprogramming, and specifically target those to reduce the effects of ageing. This approach holds promise for valuable discoveries that could open up an amazing therapeutic horizon.”
Prof Reik has recently moved to lead the Altos Labs Cambridge Institute, which is due to open at Granta Park in summer. It is the Cambridge arm of Altos Labs, which was launched with $3bn backing in January and support from the likes of Shinya Yamanaka, who will act as a scientific advisor.
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