Old Skin Cells Can Be Reprogrammed To Regain Their Youth
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We’d all like to turn the clock back sometimes. To relive an experience, undo a mistake or to bare our youthful looks once again. Alas, while many unbelievable scientific breakthroughs have occurred over the last few centuries, time travel is not one of them.
Regenerative biologists, however, are succeeding in turning the clock back on our cells – or rather, their programming.
Most recent estimates suggest that the human body comprises ~ 30 trillion cells. Each cell performs its own unique role, and collectively the cells in our body conduct the biological functions required for us to exist.
Stem cells are often referred to as cellular “raw materials”; the foundations from which specialized cells – like red blood cells or kidney cells – are made. There are several different types, including embryonic, mesenchymal and tissue-specific stem cells. For many years, regenerative biology has sought ways to convert specialized cells back into stem cells via engineering in a laboratory. These manipulated cells are known as induced pluripotent stem cells (iPSCs), and their use spans many different areas of science, including:
- Creating cell models to study healthy or diseased states
- Developing new cell-based therapeutics
- Cell-based manufacturing
A breakthrough for the field came when Professor Shinya Yamanaka discovered a method by which mature cells could be reprogramed to become pluripotent. In 2012, Yamanaka was awarded the Nobel Prize in Physiology or Medicine. This approach required the cells to be “stripped back” using specific molecules – now known as the Yamanaka factors – and takes approximately 50 days.
Unspecialized cells, while useful in many contexts, can have adverse implications. They may proliferate and form cancers, therefore there is an advantage to being able to reprogram iPSCs back into their original specialized form. Until now, this has proven challenging using available approaches.
A new method, based on the work of Yamanaka, has been developed by researchers at the Babraham Institute, Cambridge UK, to overcome this issue. Named “maturation phase transient reprograming” (MPTR), the method exposes skin cells to the Yamanaka factors for 13 days. Afterwards, the cells have lost their identity. However, when given the opportunity to grow under normal conditions, the researchers discovered via multi-omics analysis that the cells regained key hallmark characteristics of their original function, but they had been ”rejuvenated”. The method has been published in the journal eLife.
MPTR has the potential to broaden the range of stem cell applications and help us treat age-related diseases, the Babraham Institute scientists say. Technology Networks wanted to learn about this “ground-breaking development” in regenerative biology, how it has been achieved and the next steps for the research team. In this interview, we spoke with Professor Wolf Reik, lead author of the study and a renowned professor of epigenetics at the University of Cambridge, and Dr. Diljeet Gill, co-author and a postdoc in Reik’s lab, to find out more.
Molly Campbell (MC): What is regenerative biology and why is it an important field of research? What are its applications?
Diljeet Gill (DG): Regenerative biology aims to repair the damage caused by disease or injury to restore function to tissues and organs. As we get older, cells undergo a variety of changes that leads to the gradual loss of their function. As a result, tissues and organs became less functional and the risk of many diseases increases. Regenerative biology can help to reverse these changes and as a result may treat and or prevent age-related diseases.
MC: Why are we currently unable to recreate the conditions reliably to re-differentiate stem cells into all cell types?
Wolf Reik (WR): The differentiation processes for some cell types are not fully understood. As a result, we do not know all the necessary signals and appropriate timings to generate certain cell types.
MC: Can you talk about the inspiration behind developing MPTR?
WR: Complete iPSC reprograming is known to rejuvenate multiple markers of aging such as epigenetic clocks and oxidative stress, however, complete reprogramming leads to the loss of the original cell type, which can be difficult to reacquire. Our early work demonstrated that rejuvenation occurs midway during iPSC reprogramming, which suggested that complete reprogramming may not be necessary to rejuvenate cells. Instead, we may be able to rejuvenate cells by reprogramming up to this intermediate stage, which should allow cells to return to their original cell type.
MC: Can you explain exactly what the new method entails?
DG: In our method, we introduce the genes required for stem cell reprogramming to skin cells using viruses. These genes are designed in a way that they are inducible, so that we can control when they switch on or off. We then switch on the reprogramming genes for 13 days. At this point, some of the cells have started to become stem cell-like but others have not. We collect the stem cell-like cells and then switch off the reprogramming genes. After four weeks, the cells become skin cells again, but with several markers of aging rejuvenated.
MC: Why is it important to be able to reprogram cells such that they are biologically younger, but also to ensure that they can regain their specialized cell functions?
WR: Unspecialized cells are potentially harmful as they can form cancers called teratomas.
MC: Can you talk about the “age-related changes” that are removed by day 13?
WR: Several age-related changes are rejuvenated by MPTR. Epigenetic clocks are tools that predict age based on the pattern of DNA methylation (a type of mark on our DNA that doesn’t affect its sequence) and MPTR rejuvenates epigenetic clocks by around 30 years. The transcriptome (through which genes are switched on or off) also rejuvenates to a similar extent. Functional measures are also rejuvenated. Cells produce more collagen and move more quickly in artificial wound tests.
MC: Can you talk about the hallmarks of aging that you looked for in the cells? How reliable/valid are these hallmarks, and the methods that were use to study them?
DG: We examined the epigenome, in particular the pattern of DNA methylation. This was measured using the DNA methylation array, which measures the DNA methylation levels at approximately 850,000 sites in the genome. The transcriptome was measured with RNA-sequencing. Protein levels of collagen were measured with immunofluorescent staining and imaging. Migration speed was measured with an in vitro wound healing assay, where cells were grown on specialized dishes with an insert. The insert was then removed to generate a cell-free gap (the “wound”) and the dishes were imaged every 20-minutes to see how cells move into the cell-free gap.
MC: The exact molecular mechanisms behind the method are not yet fully understood. How are you hoping to unpick these mechanisms?
WR: Understanding the exact molecular mechanisms is the next step for our work. We are looking to profile cells undergoing our method in more detail, potentially by examining more timepoints to increase our temporal resolution or by using single-cell technologies to examine what is occurring in individual cells. We hope to understand what is downstream of the reprogramming factors that is responsible for eliciting rejuvenation. By uncovering such downstream regulators, we may be able to induce rejuvenation without reprogramming.
MC: Can you talk about the potential applications of this work that you are most excited about?
DG: We are very excited about the potential of our work to improve cell therapies. With our current work, rejuvenated skin cells may help treat skin conditions such as cuts, burns or ulcers. We are also excited about applying our method to other cell types such as liver, heart or brain cells, which may broaden the range of potential applications and help us treat other age-related diseases.
MC: Are there any limitations to this research that you wish to highlight?
DG: The reprogrammed genes are known to possess oncogenic properties and inappropriate expression can lead to the formation of cancer. Our work limits the expression of these genes, which should help to avoid these issues. Nevertheless, we need to assess the long-term effects of our method and whether treated cells remain stable and safe. In the future, we aim to understand the mechanisms behind rejuvenation in more detail, which may enable us to rejuvenate cells without reprogramming at all.
Professor Wolf Reik and Dr. Diljeet Gill were speaking to Molly Campbell, Senior Science Writer for Technology Networks.
