A recent study – published in Life Science Alliance – shows that pathogenic gene mutations causing a type of intractable skin disease can be eliminated from some parts of patients' skin as they age. This represents a form of natural gene therapy, say the researchers from Hokkaido University in Japan. In general, there is no fundamental treatment method capable of curing diseases caused by gene abnormality because it is difficult to remove certain genetic mutations from all affected cells. For example, Loricrin keratoderma (LK) is one such disease caused by loricrin mutations and characterized by dry, thickened, scaly skin from birth. Only symptomatic treatments are available to alleviate the conditions, which cause difficulties in patients' daily lives because doctors have not known how to treat the ailment.
The researchers observed the patients' skin for an extended period and discovered that LK patients had normal-looking skin areas dotted around their body. Tissue from those areas was examined for histology, and DNA extracted from both the epidermis and dermis were checked for loricrin mutations. The study found skin areas that looked normal were in fact skin that had returned to normal and that, surprisingly, the mutant loricrin which patients were supposed to have from birth had disappeared. Detailed analyses of the DNA sequences revealed that the mutation had disappeared due to somatic recombination, which is a type of DNA recombination that causes exchange of DNA strands that contain similar sequences. Normal skin stayed in the same location for at least several years, so the finding suggests gene mutations are eliminated from stem cells that keep providing new cells in the epidermis.
Cells with normal loricrin have higher reproduction ability and are more likely to form colonies than cells with mutant loricrin. This survival advantage could be why the normal cells became noticeable on the patients' skin. "If we could elucidate the mechanism of frequent somatic recombination occurring in epidermal cells, and could find a way to artificially induce it, that could lead to the development of a new treatment method for loricrin keratoderma, and potentially other genetic diseases," says researcher Toshifumi Nomura.
Normal Resilient Skin
Even though normal skin contains a patchwork of mutated cells, scientists have discovered that very few go on to eventually form cancer. Researchers at the Wellcome Sanger Institute and MRC Cancer Unit, University of Cambridge genetically engineered mice to show that mutant cells in skin tissue compete with each other, with only the fittest surviving. The results were published in Cell Stem Cell and suggest that normal skin in humans is more resilient to cancer than previously thought and can still function while a battle between mutated cells takes place in the tissue.
Non-melanoma skin cancer in humans includes two main types: basal cell skin cancer and squamous cell skin cancer, both of which develop in areas of the skin that have been exposed to the sun. Basal cell skin cancer is the most common type of skin cancer, whereas squamous cell skin cancer is generally faster growing. Every person who has been exposed to sunlight carries many mutated cells in their skin, and only very few of these may develop into tumors, but the reasons for this are not well understood.
Researchers have now shown for the first time that mutated cells in the skin grow to form clones that compete against each other. Many mutant clones are lost from the tissue in this competition, which resembles the selection of species that occurs in evolution. Meanwhile, the skin tissue is resilient and functions normally while being taken over by competing mutant cells. "In humans, we see a patchwork of mutated skin cells that can expand enormously to cover several millimeters of tissue,” says Professor Phil Jones, lead author from the Wellcome Sanger Institute and MRC Cancer Unit, University of Cambridge. “But why doesn't this always form cancer? Our bodies are the scene of an evolutionary battlefield. Competing mutants continually fight for space in our skin, where only the fittest survive."
Scientists used mice to model the mutated cells seen in human skin, and focused on the p53 gene - a key driver in non-melanoma skin cancers. The team created a genetic “switch” which when turned on, replaced p53 with the identical gene including the equivalent of a single letter base change. This changed the p53 protein and gave mutant cells an advantage over their neighbors. The mutated cells grew rapidly, spread and took over the skin tissue, which became thicker in appearance. However, after six months the skin returned to normal and there was no visual difference between normal skin and mutant skin.
The team then investigated the role of sun exposure on skin cell mutations. Researchers were shone very low doses of ultraviolet light - below sunburn level - onto mice with mutated p53. The mutated cells grew much faster, reaching the level of growth seen at six months in non-UV radiated clones in only a few weeks. However, despite the faster growth, cancer still did not form after nine months of exposure. "We did not observe a single mutant colony of skin cells take over enough to cause cancer, even after exposure to ultraviolet light,” added Dr. Kasumi Murai, joint first author from the Wellcome Sanger Institute. “Exposure to sunlight continually created new mutations that outcompeted the p53 mutations. We found the skin looked completely normal after we shone UV light on the mice, indicating that tissues are incredibly well-designed to tolerate these mutations and still function."
"The reason that people get non-melanoma skin cancer is because so much of their skin has been colonized by competing mutant cells over time,” added Dr. Ben Hall, senior author from the MRC Cancer Unit, University of Cambridge. “This study shows that the more we are exposed to sunlight, the more it drives new mutations and competition in our skin. Eventually the surviving mutation may evolve into a cancer."
Does Being Older Help Skin Heal With Less Scarring?
A compound called stromal cell-derived-factor-1 (SDF1) secreted in the bloodstream could be the key factor that causes wounds in older people to heal with less scarring than in younger people. Researchers from the Perelman School of Medicine at the University of Pennsylvania showed that blocking it could influence scar formation and tissue regeneration in mice and human skin, potentially providing a path to scar-less wound healing in humans. The finding - published in Cell Reports - were drawn from studies of both mice and lab-grown human skin. “Dermatologists and plastic surgeons have consistently observed that older people’s wounds heal with thinner scars than younger patients’, but until now, no one has been able to answer the question of why that’s the case,” says senior author Thomas H. Leung, MD, Ph.D., an assistant professor of dermatology at Penn.
The researchers pierced the ears of mice of different ages – the equivalent of a 12-year-old and a 70-year-old if converted to human years. The hole closed with no scar formation in older mice, while younger mice healed with a visible scar. Researchers then exchanged the blood of young mice with old mice, pierced their ears, and found that the ears of old mice now scarred. They concluded whatever was causing the scarring must be something in the blood. The team then took tissue samples from young and old mice and compared their gene expression signatures.
They identified 80 differences, but when they asked which gene products are found in the blood stream, the list narrowed to 13 suspects. One was SDF1, a signaling molecule that was previously shown to play a role in scar formation in the skin, liver, and lung, and it seemed like a promising possibility. They confirmed that SDF1 was expressed in younger mice but not older. To prove that SDF1 may be the causal factor, they created a mouse that lacked SDF1 in the skin. When SDF1 function was inactivated, even young mice began to regenerate skin, behaving, in this sense, like older mice. “This is a rare instance where aging actually improves the body’s ability to heal rather than diminishing it,” Leung added. “When we’re younger, we secrete more SDF1 into the blood stream to form scars, but as we age, we lose this ability, which allows tissue to regenerate.”
The researchers exchanged the blood between young SDF1-deficient mice and older mice and this time neither mouse scarred. The team went one step further and grew human skin in the lab, then injured it with a scalpel. Human skin also exhibited an age-dependent expression of SDF1. This work has the ability to impact the clinic relatively quickly. SDF1 inhibitors already exist on the market and are currently used as a treatment to mobilize stem cells. The researchers plan to study its use in preventing scar formation in humans.
Link Between Skin And Blood Pressure
Skin plays a surprising role in helping regulate blood pressure and heart rate, scientists at the University of Cambridge and the Karolinska Institute, Sweden discovered. While this discovery was made in mice, the researchers believe it is likely to be true also in humans. For the study - published in eLife - the researchers show that skin helps regulate blood pressure and heart rate in response to changes in the amount of oxygen available in the environment.
For the vast majority of cases of high blood pressure, which is associated with cardiovascular disease such as heart attack and stroke, there is no known cause. The condition is often associated with reduced flow of blood through small blood vessels in the skin and other parts of the body. This symptom can get progressively worse if the hypertension is not treated. Previous research has shown that when a tissue is starved of oxygen, blood flow to that tissue will increase. In such situations, this increase in blood flow is controlled in part by the HIF – Hypoxia-Inducible Factor - family of proteins.
Researchers from Cambridge and Sweden exposed mice to low-oxygen conditions to find out what role the skin plays in the flow of blood through small vessels. These mice had been genetically modified so that they are unable to produce certain HIF proteins in the skin. "Nine of 10 cases of high blood pressure appear to occur spontaneously, with no known cause," says Professor Randall Johnson from the Department of Physiology, Development and Neuroscience at the University of Cambridge. "Most research in this area tends to look at the role played by organs such as the brain, heart and kidneys, and so we know very little about what role other tissue and organs play. Our study was set up to understand the feedback loop between skin and the cardiovascular system. By working with mice, we were able to manipulate key genes involved in this loop."
The Skin’s Response To Oxygen
The researchers found that in mice lacking one of two proteins in the skin - HIF-1 or HIF-2 - the response to low levels of oxygen changed compared to normal mice and that this affected their heart rate, blood pressure, skin temperature and general levels of activity. Mice lacking specific proteins controlled by the HIFs also responded in a similar way. In addition, the researchers showed that even the response of normal, healthy mice to oxygen starvation was more complex than previously thought. In the first 10 minutes, blood pressure and heart rate rise, and this is followed by a period of up to 36 hours where blood pressure and heart rate decrease below normal levels. By around 48 hours after exposure to low levels of oxygen, blood pressure and heart rate levels had returned to normal.
Loss of the HIF proteins or other proteins involved in the response to oxygen starvation in the skin was found to dramatically change when this process starts. "These findings suggest that our skin's response to low levels of oxygen may have substantial effects on how the heart pumps blood around the body," says first author Dr. Andrew Cowburn. "Low oxygen levels - whether temporary or sustained - are common and can be related to our natural environment or to factors such as smoking and obesity. We hope that our study will help us better understand how the body's response to such conditions may increase our risk of or even cause hypertension."
"Given that skin is the largest organ in our body, it perhaps shouldn't be too surprising that it plays a role in regulating such a fundamental mechanism as blood pressure,” Johnson added. “But this suggests to us that we may need to take a look at other organs and tissues in the body and see how they, too, are implicated."
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With over 30 years of writing and editing experience for newspapers, magazines and corporate communications, Kevin Kerfoot writes about natural health, nutrition, skincare and oral hygiene for Trusted Health Products’ natural health blog and newsletters.
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