Here is an interesting one for the biology of ageing and regenerative medicine file. Recent research has shown that skin cells can be rejuvenated by up to thirty years. The idea is to induce stem cells, which are capable of becoming, with development, cells of any part of the body. Then by various processes the cells are redirected along the pathway of skin cells, hence growing new skin tissue. It strikes me that this technology could revolutionise the treatment of severe burns patients who may be able to regrow new skin tissue. Fire fighters will be pleased.
https://www.sciencedaily.com/releases/2022/04/220408083901.htm?utm_source=gnaa
“Babraham Institute
Summary:
Scientists have developed a new technique for rejuvenating skin cells. This technique has allowed researchers to rewind the cellular biological clock by around 30 years according to molecular measures, significantly longer than previous reprogramming methods. The partially rejuvenated cells showed signs of behaving more like youthful cells in experiments simulating a skin wound. This research, although in early stages, could eventually have implications for regenerative medicine, especially if it can be replicated in other cell types.
Research from the Babraham Institute has developed a method to 'time jump' human skin cells by 30 years, turning back the ageing clock for cells without losing their specialised function. Work by researchers in the Institute's Epigenetics research programme has been able to partly restore the function of older cells, as well as rejuvenating the molecular measures of biological age. The research is published today in the journal eLife and whilst at an early stage of exploration, it could revolutionise regenerative medicine.
What is regenerative medicine?
As we age, our cells' ability to function declines and the genome accumulates marks of ageing. Regenerative biology aims to repair or replace cells including old ones. One of the most important tools in regenerative biology is our ability to create 'induced' stem cells. The process is a result of several steps, each erasing some of the marks that make cells specialised. In theory, these stem cells have the potential to become any cell type, but scientists aren't yet able to reliably recreate the conditions to re-differentiate stem cells into all cell types.
Turning back time
The new method, based on the Nobel Prize winning technique scientists use to make stem cells, overcomes the problem of entirely erasing cell identity by halting reprogramming part of the way through the process. This allowed researchers to find the precise balance between reprogramming cells, making them biologically younger, while still being able to regain their specialised cell function.
In 2007, Shinya Yamanaka was the first scientist to turn normal cells, which have a specific function, into stem cells which have the special ability to develop into any cell type. The full process of stem cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called 'maturation phase transient reprogramming', exposes cells to Yamanaka factors for just 13 days. At this point, age-related changes are removed and the cells have temporarily lost their identity. The partly reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. Genome analysis showed that cells had regained markers characteristic of skin cells (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells.
Age isn't just a number
To show that the cells had been rejuvenated, the researchers looked for changes in the hallmarks of ageing. As explained by Dr Diljeet Gill, a postdoc in Wolf Reik's lab at the 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."
Researchers looked at multiple measures of cellular age. The first is the epigenetic clock, where chemical tags present throughout the genome indicate age. The second is the transcriptome, all the gene readouts produced by the cell. By these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger compared to reference data sets.
The potential applications of this technique are dependent on the cells not only appearing younger, but functioning like young cells too. Fibroblasts produce collagen, a molecule found in bones, skin tendons and ligaments, helping provide structure to tissues and heal wounds. The rejuvenated fibroblasts produced more collagen proteins compared to control cells that did not undergo the reprogramming process. Fibroblasts also move into areas that need repairing. Researchers tested the partially rejuvenated cells by creating an artificial cut in a layer of cells in a dish. They found that their treated fibroblasts moved into the gap faster than older cells. This is a promising sign that one day this research could eventually be used to create cells that are better at healing wounds.
In the future, this research may also open up other therapeutic possibilities; the researchers observed that their method also had an effect on other genes linked to age-related diseases and symptoms. The APBA2 gene, associated with Alzheimer's disease, and the MAF gene with a role in the development of cataracts, both showed changes towards youthful levels of transcription.
The mechanism behind the successful transient reprogramming is not yet fully understood, and is the next piece of the puzzle to explore. The researchers speculate that key areas of the genome involved in shaping cell identity might escape the reprogramming process.
Diljeet concluded: "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."
Professor Wolf Reik, a group leader in the Epigenetics research programme who has recently moved to lead the Altos Labs Cambridge 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."
Journal Reference:
- Diljeet Gill, Aled Parry, Fátima Santos, Hanneke Okkenhaug, Christopher D Todd, Irene Hernando-Herraez, Thomas M Stubbs, Inês Milagre, Wolf Reik. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. eLife, 2022; 11 DOI: 7554/eLife.71624
Abstract
Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming, somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first 'maturation phase transient reprogramming' (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells temporarily lose and then reacquire their fibroblast identity during MPTR, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that more extensive reprogramming does not necessarily result in greater rejuvenation but instead that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.”