Fibrotic scar 14d after spinal cord injury, red – Col1a1+ perivascular fibroblast derived cells Photo: Daniel Holl
New research has found that scar formation after spinal cord injuries is more complex than previously thought. Scientists at Karolinska Institutet have identified two types of perivascular cells as key contributors to scar tissue, which hinders nerve regeneration and functional recovery. These findings, published in Natural Neuroscience, are also relevant for other brain and spinal cord injuries and could lead to targeted therapies for reducing scarring and improving outcomes.
The central nervous system (CNS) has very limited healing abilities. Injuries or autoimmune diseases like multiple sclerosis often lead to permanent functional deficits.
Regardless of the injury’s cause, the body responds by forming a boundary around the damaged tissue, which eventually becomes permanent scar tissue.
Two contributing cell types
While scar tissue seals the damaged area, it also prevents functional repair. After spinal cord injuries, scar tissue blocks the regeneration of nerve fibers that connect the brain with the body, resulting in paralysis after severe injuries.
The research team led by Christian Göritz at Karolinska Institutet has made significant progress in understanding how scar tissue forms in the CNS. The group now identified two distinct types of perivascular cells, which line different parts of blood vessels, as the major contributors to fibrotic scar tissue after spinal cord injury. Depending on the lesion’s location, the two identified cell types contribute differently.
“We found that damage to the spinal cord activates perivascular cells close to the damaged area and induces the generation of myofibroblasts, which consequently form persistent scar tissue,” explains first author Daniel Holl, researcher at the Department of Cell and Molecular Biology.
By examining the process of scar formation in detail, the researchers hope to identify specific therapeutic targets to control fibrotic scarring.
By treating skin scars in three volunteers with hair follicle transplants, researchers found that the scarred skin began to behave more like uninjured skin. According to the results published in Nature Regenerative Medicine, the scarred skin harboured new cells and blood vessels, remodelled collagen to restore healthy patterns, and even expressed genes found in healthy unscarred skin.
The findings could lead to better treatments for scarring both on the skin and inside the body, leading to hope for patients with extensive scarring, which can impair organ function and cause disability.
Lead author Dr Claire Higgins, of Imperial’s Department of Bioengineering, said: “After scarring, the skin never truly regains its pre-wound functions, and until now all efforts to remodel scars have yielded poor results. Our findings lay the foundation for exciting new therapies that can rejuvenate even mature scars and restore the function of healthy skin.”
Hope in hair
Scar tissue in the skin lacks hair, sweat glands, blood vessels and nerves, impairing temperature regulation and sensation. Scarring can also hinder movement as well as potentially causing discomfort and emotional distress.
Compared to scar tissue, healthy skin undergoes constant remodelling by the hair follicle. Hairy skin heals faster and scars less than non-hairy skin- and hair transplants had previously been shown to aid wound healing. Inspired by this, the researchers hypothesised that transplanting growing hair follicles into scar tissue might induce scars to remodel themselves.
To test their hypothesis, Imperial researchers worked with Dr Francisco Jiménez, lead hair transplant surgeon at the Mediteknia Clinic and Associate Research Professor at University Fernando Pessoa Canarias, in Gran Canaria, Spain. They transplanted hair follicles into the mature scars on the scalp of three participants in 2017. The researchers selected the most common type of scar, called normotrophic scars, which usually form after surgery.
They took and microscope imaged 3mm-thick biopsies of the scars just before transplantation, and then again at two, four, and six months afterwards.
The researchers found that the follicles inspired profound architectural and genetic shifts in the scars towards a profile of healthy, uninjured skin.
Dr Jiménez said: “Around 100 million people per year acquire scars in high-income countries alone, primarily as a result of surgeries. The global incidence of scars is much higher and includes extensive scarring formed after burn and traumatic injuries. Our work opens new avenues for treating scars and could even change our approach to preventing them.”
Architects of skin
After transplantation, the follicles continued to produce hair and induced restoration across skin layers.
Scarring causes the epidermis to thin out, leaving it vulnerable to tears. At six months post-transplant, the epidermis had doubled in thickness alongside increased cell growth, bringing it to around the same thickness as uninjured skin.
The next skin layer down, the dermis, is populated with connective tissue, blood vessels, sweat glands, nerves, and hair follicles. Scar maturation leaves the dermis with fewer cells and blood vessels, but after transplantation the number of cells had doubled at six months, and the number of vessels had reached nearly healthy-skin levels by four months. This demonstrated that the follicles inspired the growth of new cells and blood vessels in the scars, which are unable to do this unaided.
Scarring also increases the density of collagen fibres, causing them to align and make the scar stiffer. The hair transplants reduced the fibre density, allowing them to form a healthier, ‘basket weave’ pattern, which reduced stiffness – a key factor in tears and discomfort.
The authors also found that after transplantation, the scars expressed 719 genes differently to before. Genes that promote cell and blood vessel growth were expressed more, while genes that promote scar-forming processes were expressed less.
Underling mechanism still unknown
It is not known how exactly the transplants brought about the change. Having of a hair follicle in the scar was cosmetically acceptable for the participants as the scars were on the scalp. The researchers are now working to uncover the underlying mechanisms so they can develop therapies that remodel scar tissue towards healthy skin, without the hair follicle transplant. They can then test their findings on non-hairy skin, or on organs like the heart, which can suffer scarring after heart attacks, and the liver, which can suffer scarring through fatty liver disease and cirrhosis.
Dr Higgins said: “This work has obvious applications in restoring people’s confidence, but our approach goes beyond the cosmetic as scar tissue can cause problems in all our organs.
“While current treatments for scars like growth factors focus on single contributors to scarring, our new approach tackles multiple aspects, as the hair follicle likely delivers multiple growth factors all at once that remodel scar tissue. This lends further support to the use of treatments like hair transplantation that alter the very architecture and genetic expression of scars to restore function.”
Chemical peels are a common treatment for acne scars, but a study published in the Journal of Clinical and Aesthetic Dermatology finds that, for patients with dark skin, microneedling is a significantly more effective treatment.
Researchers randomly assigned 60 patients with acne scars and dark skin (Fitzpatrick Skin Phototype IV to VI) to treatment with either 35% glycolic acid chemical peels or microneedling, both administered every two weeks for 12 weeks.
Microneedling therapy is a controlled skin injury that utilises instruments containing rows of thin needles that penetrate the dermis to a uniform depth. This induces rapidly-healing micropunctures with subsequent stimulation of collagen and elastin fibre production, resulting in skin remodelling.
Microneedling was initially developed as a tool for skin rejuvenation. However, it is now being used for a number of indications, which include: various forms of scars, alopecias, drug delivery, hyperhidrosis, stretch marks, and more. It is occasionally combined with delivery of radiofrequency energy, which is thought to enhance dermal remodelling and clinical effects. Despite its widespread use, data on the efficacy of microneedling are lacking.
Chemical peels involve applying a solution to the skin that removes the top layers.
Treatment produced an improvement of two points or more on the Goodman and Baron Scarring Grading System in 33% of patients who received chemical peels and 73% of patients who underwent microneedling.
“Based on the results of this study, patients whose darker skin precludes the use of stronger chemical peels, which can permanently discolour darker skin, should treat acne scars with microneedling,” said the study’s senior author Babar Rao, a professor of dermatology and pathology at Robert Wood Johnson Medical School. “For patients with lighter skin who can use stronger peels without risk of discoloration, chemical peels might still be the best option for some.”
A new wound dressing technology that can stop bleeding while preventing infection and scarring using a single material, has been developed. This technology also has potential applications in drug delivery, among other areas.
“Scarring is one of the worst consequences of severe wounds,” said Xiaoyang Wu, an associate professor in the Ben May Department of Cancer Research at the University of Chicago, noting that scar tissue formation is particularly common in human skin.
The researchers used a material science approach to develop a new method to overcome scarring, by impeding collagen synthesis by blocking transforming growth factor beta (TGF-β) – a cytokine that plays an important role in cell signaling, both in skin wound repair and tissue fibrosis.
“Increasing evidence suggests TGF-β is important in early phase wound repair for wound closure. But, later on, the signal may promote and enhance scarring,” Prof Wu said. This makes timing crucial. “We cannot simply block the signal, because that would slow down wound healing and would be dangerous for the patient,” he explained.
To get around this, the researchers came up with a delayed-release system combining a sutureless wound closure hydrogel material with a biodegradable microcapsule system, enabling them to control the release of the TGF-β inhibitor. “In this way, we can enhance skin wound repair and after 7-14 days can release the inhibitor that blocks the skin scarring process at the same time by using one material,” Prof Wu added.
At present, treatment of scarring is not ideal with little besides cosmetic surgery, and little can be done to prevent scar formation if a patient experiences a deep or messy wound. “The system we developed is very convenient for application,” said Wu, adding that the system has many possible future applications, such as drug delivery.
“We believe the novel system will have potential clinical importance in the future,” he said. To this end, the next steps include filing an investigational new drug (IND) application with the US Food and Drug Administration (FDA). Consistent manufacturing of the material is necessary and the researchers are exploring collaborations with pharmaceutical companies to move the research forward.
Since the system is a biocompatible material with adhesive properties, Wu said it has internal applications as well, adhering to and closing bleeding arteries and cardiac walls after irradiation with UV light. This was demonstrated in animal models, suggesting significant advantages as a traumatic wound sealant.
“Normal wound binding material does work well,” said Wu, noting that fibres are the most reliable material currently available, which, like surgical glue, is less biocompatible. “Biocompatibility is a significant advantage of our system,” he explained, “It is superior compared to current existing materials.”
