A pilot clinical study involving three volunteers has shown how scarred skin can start to behave more like uninjured skin when treated using hair follicle transplants. The small study, carried out by researchers at Imperial College London in collaboration with specialists in Spain, showed how hair follicle transplants prompted the remodeling of skin scars, which supported new cells and blood vessels, remodeled collagen and collagen patterning, and expressed genes more typically expressed in healthy, unscarred skin.
The findings, the team suggested, could lead to better treatments for scarring both on the skin and on internal organs, leading to hope for patients with extensive scarring, which can impair organ function and cause disability.
Claire Higgins, PhD, at 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.” Higgins is lead author of the team’s published paper in Nature Regenerative Medicine, which is titled, “Anagen hair follicles transplanted into mature human scars remodel fibrotic tissue,” in which the team concluded, “The results of this study lay the foundation for designing therapeutic strategies that dynamically remodel mature human scars and induce a long-lasting shift towards skin regeneration by mimicking the natural ability of hair follicles to remodel skin.”
The physiological endpoint of wound repair in humans leads to an accumulation of incompletely remodeled fibrotic tissue known as a scar, the researchers explained. Scar tissue in the skin lacks hair, sweat glands, blood vessels, and nerves, which are vital for regulating body temperature and detecting pain and other sensations. Scarring can also impair movement as well as potentially causing discomfort and emotional distress. However, the authors wrote, “Despite the substantial impact of skin scarring on patients and the healthcare system, there is a lack of strategies to prevent scar formation, let alone methods to remodel mature scars … Multiple strategies have been tested to minimize scarring, but despite years of efforts, there is no effective method to remodel mature scars.”
In comparison with “incompletely remodeled” scar tissue, healthy skin undergoes constant remodeling during the growth (anagen) stage of the hair follicle cycle. Hairy skin heals faster and scars less than non-hairy skin, and hair transplants have previously been shown to aid wound healing. The researchers hypothesized that transplanting growing hair follicles into scar tissue might also induce scars to remodel themselves.
They took advantage of hair follicle transplantation procedures performed routinely in hair transplantation clinics, by which anagen hair follicles are transplanted into scalp scars, and designed a pilot clinical study to test their hypothesis. “… we tested if hair follicles transplanted into human scars can facilitate tissue regeneration and actively remodel fibrotic tissue, similar to how they remodel the healthy skin,” they explained.
For the trial, the Imperial researchers worked with Francisco Jiménez, MD, lead hair transplant surgeon at the Mediteknia Clinic and associate research professor at University Fernando Pessoa Canarias, in Gran Canaria. In 2017, the researchers transplanted hair follicles into mature scars on the scalps of three participants. The researchers selected the most common type of scar, called normotrophic scars, which usually form after surgery. “While previous work explored the role of anagen hair follicles in wound closure, to our knowledge, this current study is the first to test the ability of hair follicles to alter the morphology and transcriptional signature of scar tissue created after the wound has closed,” they stated.
As part of their evaluation, the investigators took and microscope imaged 3 mm-thick biopsies of the scars just before transplantation, and then again at two, four, and six months after follicle transplantation. The researchers found that the transplanted follicles inspired profound architectural and genetic shifts in the fibrotic tissue toward a profile of healthy, uninjured skin. After transplantation, the follicles also continued to produce hair and induced restoration across skin layers.
Scarring causes the outermost layer of skin—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 six months after transplantation the number of cells had doubled, and the number of vessels had reached nearly healthy-skin levels by four months. This finding demonstrated that the follicles inspired the growth of new cells and blood vessels in the scars, which are unable to do this unaided. “We found that hair follicle transplantation induced an increase in the epidermal thickness, interdigitation of the epidermal dermal junction, dermal cell density, and blood vessel density,” they wrote.
Scarring increases the density of collagen fibers—a major structural protein in skin—which causes them to align such that scar tissue is stiffer than healthy tissue. The hair transplants reduced the density of the fibers, which allowed them to form a healthier, “basket weave” pattern, which reduced stiffness—a key factor in tears and discomfort. “Remodeling of collagen type I fibers reduced the total collagen fraction, the proportion of thick fibers, and their alignment,” the investigators reported.
The authors also found that more than 700 genes were differentially expressed by the scar tissue following transplantation. “Using Transcriptomic Analysis Console, we performed a one-way ANOVA analysis on the dataset and identified 719 genes that were differentially (|fold change| > 1.5) and significantly (P < 0.01, FDR < 0.01) regulated after hair follicle transplantation into mature scars.” Genes that promote cell and blood vessel growth were expressed more, while genes that promote scar-forming processes were expressed less.
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.”
The researchers are unsure precisely how the transplants facilitated such a change. In their study, the presence of a hair follicle in the scar was cosmetically acceptable as the scars were on the scalp. The aim is to continue to work to uncover the underlying mechanisms so that it might be possible to develop therapies that remodel scar tissue towards healthy skin, but without requiring transplantation of a hair follicle and growth of a hair fiber. The scientists 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.
As Higgins stated, “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.” The authors added, “The ability to drive long-lasting changes to established fibrotic tissue through paracrine signaling opens up intriguing possibilities for new regenerative approaches.”
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.”
Higgins continued, “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.” The researchers concluded, “Ultimately, we hope this work will inspire therapeutic strategies designed to capture the combinatorial signaling that likely underpins the ability of hair follicles to actively remodel fibrotic tissue, in turn bringing us one step closer to impactful therapies for fibrotic tissue.”
