A new study from Karolinska Institutet and the Chinese Academy of Medical Sciences has identified an RNA molecule that is important for skin wound healing. The research, published in Nature Communications, may have implications for the treatment of hard-to-heal wounds.
The study focuses on the molecular processes in wound healing that regulate the transition from inflammation to a proliferative phase, where new cells form to repair damaged tissue. Researchers have now mapped lncRNA (long non-coding RNA molecules) in human skin wounds in tissue samples from Karolinska University Hospital, identifying a key regulator in wound healing.
“Our study reveals that the lncRNA molecule SNHG26 plays a pivotal role in guiding skin cells through the stages of wound healing, from an inflammatory stage to a healing phase,” explains Ning Xu Landén, docent at the Department of Medicine, Solna, Karolinska Institutet.
The researchers also used mouse models to uncover how this molecule interacts with genes involved in inflammation and tissue regeneration. In mice lacking SNHG26, wound healing was delayed, emphasising the molecule’s importance in the balance between inflammation and tissue repair. The discovery paves the way for new therapeutic approaches for acute and chronic wounds.
“By targeting SNHG26, we may be able to accelerate healing and reduce complications, particularly in chronic wounds where prolonged inflammation is a major problem,” says Ning Xu Landén.
Scientists have uncovered a key step in the wound healing process that becomes disabled in diseases like diabetes and ageing. Importantly, the research published in Nature reveals a molecule involved in the healing of tissues that leads to a drastic acceleration of wound closure, up to 2.5 times faster, and 1.6 times more muscle regeneration.
The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective. This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury. Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context. However, how neuro–immune interactions affect tissue repair and regeneration following acute injury was unclear.
Lead researcher, Associate Professor Mikaël Martino, from Monash University’s Australian Regenerative Medicine Institute (ARMI) in Melbourne, Australia, said the discovery “could transform regenerative medicine, because it sheds light on the crucial role of sensory neurons in orchestrating the repair and regeneration of tissues, offering promising implications for improving patient outcomes.”
The cost of managing poorly healing wounds costs around $250 billion a year.
“In adults with diabetes alone – where poor blood flow can lead to quickly worsening wounds that are often very slow or impossible to heal – the lifetime risk of developing a diabetic foot ulcer (DFU), the most common diabetes-related wound, is 20 to 35 per cent and this number is rising with increased longevity and medical complexity of people with diabetes,” co-lead author, ARMI’s Dr Yen-Zhen Lu said.
Nociceptive sensory neurons, also called nociceptors, are the nerves in our body that sense pain.
These neurons alert us to potentially damaging stimuli in tissues by detecting dangers like tissue damage, inflammation, extremes in temperature, and pressure.
The researchers discovered that, during the healing process, sensory neuron endings grow into injured skin and muscle tissues, communicating with immune cells through a neuropeptide called calcitonin gene-related peptide (CGRP).
“Remarkably, this neuropeptide acts on immune cells to control them, facilitating tissue healing after injury,” Associate Professor Martino said.
Importantly they found that sensory neurons are crucial to the dissemination of CGRP because they showed that the selective removal of sensory neurons in mice reduce CGRP and significantly impairs skin wound healing and muscle regeneration following injury.
When the scientists administered an engineered version of CGRP to mice with neuropathy similar to that seen in diabetic patients, it led to rapid wound healing and muscle regeneration.
According to Associate Professor Martino, these findings hold significant promise for regenerative medicine, particularly for the treatment of poorly-healing tissues and chronic wounds.
“By harnessing neuro-immune interactions, the team aims to develop innovative therapies that address one of the root causes of impaired tissue healing, offering hope to millions,” he said.
“This study has uncovered significant implications for advancing our understanding of the tissue healing process after acute injury. Harnessing the potential of this neuro-immuno-regenerative axis opens new avenues for effective therapies, whether as standalone treatments or in combination with existing therapeutic approaches. “
Researchers in South Korea have achieved a ground-breaking milestone in tissue regeneration with a technology that utilises autologous blood to produce three-dimensional microvascular implants. These implants hold immense potential for various applications requiring vascular regeneration, including the treatment of chronic wounds in conditions such as diabetes, as well as the potential for scarless healing.
Led by Professor Joo H. Kang from the Department of Biomedical Engineering at UNIST, the team successfully developed a microfluidic system capable of processing blood into an artificial tissue scaffold. Unlike previous methods based on cell-laden hydrogel patches using fat tissues or platelet-rich plasma, this innovative approach enables the creation of robust microcapillary vessel networks within skin wounds. The utilisation of autologous whole blood ensures compatibility and promotes effective wound healing.
Creating optimal stiffness
The technology, described in Advanced Materials, leverages microfluidic shear stresses to align bundled fibrin fibres along the direction of blood flow streamlines while activating platelets. This alignment and activation process results in moderate stiffness within the microenvironment – optimal conditions for facilitating endothelial cell maturation and vascularisation. When applied as patches to rodent dorsal skin wounds, these implantable vascularided engineered thrombi (IVETs) demonstrated superior wound closure rates (96.08 ± 1.58%), increased epidermis thickness, enhanced collagen deposition, hair follicle regeneration, reduced neutrophil infiltration, and accelerated wound healing through improved microvascular circulation.
Chronic wounds pose significant challenges as they often fail to heal properly over time and can lead to complications associated with diabetes and vascular diseases. In severe cases, they may result in sepsis due to insufficient oxygen supply and nutrients caused by loss of blood vessels.
By harnessing the power of microfluidic technology, Professor Kang’s team transformed autologous blood into IVETs suitable for transplantation. These IVETs were implanted into full-thickness skin wounds in experimental mice, resulting in rapid and scarless recovery of the entire damaged area. The study demonstrated successful regeneration of blood vessels within the wound site, facilitated movement of immune cells crucial for wound healing, and accelerated overall recovery.
Furthermore, the team evaluated the efficacy of IVET transplantation by infecting the skin damage area with methicillin-resistant Staphylococcus aureus (MRSA). When artificial blood clots made from autologous blood were implanted into infected mice, quick vascular recovery was observed alongside enhanced migration of proteins and immune cells to combat bacterial infection. Additionally, collagen formation and hair follicle regeneration occurred without scarring.
These ground-breaking findings pave the way for advanced techniques in tissue engineering and wound healing using autologous blood-based implants. With further development and refinement, this technology holds tremendous potential to revolutionise treatment strategies for chronic wounds while contributing to advancements in regenerative medicine.
Researchers have discovered that, counterintuitively, certain cells move faster in thicker fluid – such as mucus as opposed to blood – because their ruffled edges sense the viscosity of their environment and adapt to increase their speed.
The researchers’ combined results in cancer and fibroblast cells suggest that the viscosity of a cell’s surrounding environment is an important contributor to disease. The findings, published in Nature Physics, may help explain tumour progression, scarring in mucus-filled lungs affected by cystic fibrosis, and the wound-healing process.
“This link between cell viscosity and attachment has never been demonstrated before,” noted Sergey Plotnikov, assistant professor at the University of Toronto and a co-corresponding author of the study. “We found that the thicker the surrounding environment, the stronger the cells adhere to the substrate and the faster they move – much like walking on an icy surface with shoes that have spikes, versus shoes with no grip at all.”
Understanding why cells behave in this surprising way is important because cancer tumours create a viscous environment, which means spreading cells can move into tumours faster than non-cancerous tissues. Since the researchers observed that cancer cells speed up in a thickened environment, they concluded that the development of ruffled edges in cancer cells may contribute to cancer spreading to other areas of the body.
Targeting the spreading response in fibroblasts, on the other hand, may reduce tissue damage in the mucus-filled lungs affected by cystic fibrosis. Because ruffled fibroblasts move quickly, they are the first type of cells to move through the mucus to the wound, contributing to scarring rather than healing. These results also imply that cell movement might be controlled by changing the viscosity of the lung’s mucus.
“By showing how cells respond to what’s around them, and by describing the physical properties of this area, we can learn what affects their behaviour and eventually how to influence it,” says Ernest Iu, PhD student at the University of Toronto and study co-author.
Plotnikov added, “For example, perhaps if you put a liquid as thick as honey into a wound, the cells will move deeper and faster into it, thereby healing it more effectively.”
Asst Prof Plotnikov and Iu used advanced microscopy techniques to measure the traction that cells exert to move, and changes in structural molecules inside the cells. They compared cancer and fibroblast cells, which have ruffled edges, to cells with smooth edges. They determined that ruffled cell edges sense the thickened environment, triggering a response that allows the cell to pull through the resistance – the ruffles flatten down, spread out and latch on to the surrounding surface.
The experiment originated at Johns Hopkins, where assistant professor Yun Chen, lead author of the study, and Matthew Pittman, PhD student and first author, were first examining the movement of cancer cells. Pittman created a viscous, mucus-like polymer solution, deposited it on different cell types, and saw that cancer cells moved faster than non-cancerous cells when migrating through the thick liquid. To further probe this behaviour, Asst Prof Chen collaborated with U of T’s Plotnikov, who specialises in the push and pull of cell movement.
Plotnikov was amazed at the change in speed going into thick, mucus-like liquid. “Normally, we’re looking at slow, subtle changes under the microscope, but we could see the cells moving twice as fast in real time, and spreading to double their original size,” he explained.
Typically, cell movement depends on myosin proteins, which help muscles contract. Asst Prof Plotnikov and Iu reasoned that stopping myosin would prevent cells from spreading, however were surprised when evidence showed the cells still sped up despite this action. They instead found that columns of the actin protein inside the cell, which contributes to muscle contraction, became more stable in response to the thick liquid, further pushing out the edge of the cell.
The teams are now investigating how to slow the movement of ruffled cells through thickened environments, which may open the door to new treatments for people affected by cancer and cystic fibrosis.
Scanning electron microscope image of red blood cells, platelets (green) and T cells (orange). . Image courtesy of Dennis Kunkel, Dennis Kunkel Microscopy, Inc. Part of the exhibit Life:Magnified by ASCB and NIGMS.
New research shows that platelets at a wound site can sense where they are within a blood clot they are and that they can remodel their surroundings accordingly.
Platelets are key to initiating wound healing and the formation of blood clots (thrombus). Fibroblasts are connective tissue cells that are essential for the later stages of wound healing. Fibroblasts invade the clot that has been formed and produce vital proteins, including fibronectin, that then form a structural framework to build the new tissue needed to heal.
This new study, published in Science Advances, indicates that platelets can also form a provisional fibronectin matrix in their surroundings, similar to what fibroblasts do in the later stages of wound healing. This has potential implications for how the integrity of blood clots might be maintained during vascular repair.
Commenting on the discovery, lead author Dr Ingmar Schoen said: “We have identified an additional unexpected role for the most prominent platelet adhesion receptor. Our results show that platelets not only form the clot but also can initiate its remodelling by erecting a fibrous scaffold. This finding challenges some existing paradigms in the field of wound healing, which is dominated by research on fibroblasts.”
The researchers made use of super-resolution microscopy, a powerful imaging technique which enables much finer resolution of structures inside or around cells in vitro. To develop this finding further, in vivo observation of this platelet behaviour will be necessary.
“Without super-resolution microscopy, this discovery would not have been possible,” Dr Schoen noted.
Researchers have shown that smartphone pictures of post-surgical wounds taken by patients and then assessed by clinicians help spot infections early on.
These ‘surgery selfies’ were associated with a reduced number of GP visits and improved access to advice among patients who took them. This practice could help manage surgical patients’ care while they recover.
Death within 30 days of surgery is the third largest cause of mortality globally. More than a third of postoperative deaths are associated with surgical wound infections.
In the study, published in NPJ Digital Medicine, University of Edinburgh researchers conducted a randomised clinical trial involving 492 emergency abdominal surgery patients to determine if photos from smartphones and questions on symptoms of infection could be used to diagnose wound infections early.
One group of 223 patients were contacted on days three, seven and 15 after surgery and directed to an online survey, where they were asked about their wound and any symptoms they were experiencing. Then they were asked to take a picture of their wound and upload it.
A surgical team member assessed the photographs and patients’ responses were assessed for signs of wound infection. They followed up with patients 30 days after surgery to find out if they had been subsequently diagnosed with an infection.
A second group of 269 received standard care and were contacted 30 days after surgery to find out if they had been diagnosed with an infection.
No significant difference between groups was seen in the overall time it took to diagnose wound infections in the 30-days after surgery.
However, the smartphone group was nearly four times more likely to have their wound infection diagnosed within seven days of their surgery compared to the routine care group. They also had fewer GP visits and reported a better experience of trying to access post-operative care.
The research team is now conducting a follow-up study to determine how this can be best put into practice for surgical patients around the country. Artificial intelligence will also be used to help the clinical team in assessing the possibility of wound infection.
Professor Ewen Harrison, Professor of Surgery and Data Science, who led the research said: “Our study shows the benefits of using mobile technology for follow-up after surgery. Recovery can be an anxious time for everybody. These approaches provide reassurance – after all, most of us don’t know what a normally healing wound looks like a few weeks after surgery. We hope that picking up wound problems early can result in treatments that limit complications.”
Dr. Kenneth McLean, who co-led the research said: “Since the COVID-19 pandemic started, there have been big changes in how care after surgery is delivered. Patients and staff have become used to having remote consultations, and we’ve shown we can effectively and safely monitor wounds after surgery while patients recover at home – this is likely to become the new normal.”
A new study from Vanderbilt University researchers has revealed how cells detect and react to wounds.
The epithelial cells which cover the body and its organs, must be able to heal wounds, as they are constantly exposed to insults and abrasion. “When these cells detect a wound nearby, they change their behaviours,” said study co-leader Professor Andrea Page-McCaw in the Department of Cell and Developmental Biology. “They transition from stationary, nondividing, noninvasive cells to cells that migrate, divide and invade.” This also describes the behaviors of cancer cells, which adopt wound-healing behaviours without any wound.
The researchers began with focusing on epithelial cells’ first known reaction of to a nearby wound: an increase in calcium levels, which typically occurs within a minute of wounding.
“We were able to connect the response of these cells directly to the cellular damage inherent in wounding,” Prof Page-McCaw said. “We found that wounds destroy cells, causing them to leak or even burst, and some of their contents get out. Outside of cells, tissues have a detector molecule ready to sense these cellular contents. When they do, proteases in the cellular contents chop up the detector molecule into smaller pieces, which spread to nearby cells. This activates receptors on the cells’ surfaces, giving them the information that a wound is nearby.”
Successful and efficient wound healing is key for recovery from trauma or surgery, and this study improves the understanding of how wounds are recognised by epithelial cells and how this leads to wound healing. This will help develop therapeutics that can address this health issue.
Slow wound healing time can be caused by a number of factors, such as diabetes, and can lead to infection and declining health. By figuring out how to downregulate these wound-healing behaviours in combination with other cancer interventions, this work offers insights that could help combat cancer’s adoption of this mechanism.
The researchers will next focus on how cells use the information they receive about the presence of a wound, specifically how the information is encoded in the calcium signal dynamics and then converted into migration, proliferation and changes in cell- and tissue-level mechanics. “Now that we have a solid understanding of how the presence of a wound is first signaled to nearby cells, we can ask a lot of interesting follow-up questions,” said study co-leader Shane Hutson, chair of the Department of Physics and Astronomy and professor of physics and biological sciences. “How much information is present in those signals? Can cells interpret the signals to know how large the wound is or how far they are from the wound? Do they use the way the dynamic signals change with time to make that measurement? What are the detailed mechanisms by which the signals then get turned into cellular actions?”
Journal information: James T. O’Connor et al, Proteolytic activation of Growth-blocking peptides triggers calcium responses through the GPCR Mthl10 during epithelial wound detection, Developmental Cell (2021). DOI: 10.1016/j.devcel.2021.06.020
