A preclinical study in mice and human tissue has uncovered a molecular pathway that may help to explain why wounds inside the mouth can heal quickly and without scars. The researchers, co-led by teams at Cedars-Sinai, Stanford Medicine and the University of California, San Francisco (UCSF), used single-cell RNA sequencing (scRNA-seq) to analyze and compare tissue samples from the lining of the mouth—the oral mucosa—and the facial skin of laboratory mice following wounding.
In the oral mucosa they found a signaling pathway between cells, involving a protein called GAS6 and an enzyme called AXL, which blocks a different cellular pathway, known as FAK, that promotes scarring. When the investigators inhibited the AXL enzyme in the laboratory mice, the oral mucosa wounds’ healing worsened, making them more like skin wounds. When AXL was stimulated in the skin wounds, they healed much like oral mucosa wounds, regenerating tissue more efficiently.
The results hint at a strategy that could help to limit fibrosis and scarring in injuries outside of the mouth. If confirmed in humans, the findings could one day lead to treatments that enable rapid, scarless recovery from skin wounds on different parts of the body.
The team, co-led by Ophir Klein, MD, PhD, executive vice dean of Children’s Health at Cedars-Sinai, executive director of Cedars-Sinai Guerin Children’s, the David and Meredith Kaplan Distinguished Chair in Children’s Health, reported on their findings in Science Translational Medicine, in a paper titled “Growth arrest specific–6 and angiotoxin receptor–like signaling drive oral regenerative wound repair.” In their paper the team stated, “Our demonstration that AXL and FAK expression act as indicators of regeneration versus fibrosis, respectively, lends our study therapeutic potential.”
Human skin can repair itself after injuries, but not without producing scar tissue. These scars can diminish the long-term function of the skin, and scars on areas such as the face can also be an aesthetic concern for patients. Currently, there aren’t any treatments that can prevent facial scarring or erase scars after they’ve formed. “The main barrier to the development of effective scarring treatments is our limited understanding of the molecular mechanisms underpinning scar formation and the mechanisms that govern repair without scarring,” the authors explained.
Searching for scar-preventing therapies, Klein and colleagues took inspiration from the oral mucosa. The oral mucosa repairs wounds faster and more efficiently than any other barrier site in the adult mammalian body and can heal without scarring in just one to three days, the authors further noted. “Oral wounds heal at nearly three times the rate of matched dermal wounds, exhibiting a much lower inflammatory response and reduced or no scarring,” they stated. But despite this “remarkable regenerative capacity of the oral mucosa,” the cellular and molecular mechanisms that regulate this rapid regeneration aren’t clear. “Our research began with two questions: Why does your mouth heal so much better than your skin?” said Klein, “[…] And if we figure that out, can we use that information therapeutically?”
To uncover the secrets of wound-healing in the oral mucosa, the team compared mouse oral mucosal fibroblasts (OMFs) to facial skin fibroblasts (FAFs), across the time course of wound healing. They found that the oral mucosal fibroblasts suppressed fibrosis and the enzyme FAK through a signaling pathway involving the protein AXL. Knocking out AXL revived FAK activity and led to scarring after oral injuries in mice.
Conversely, stimulating AXL in wounds on the face using the protein GAS6 skewed wound healing towards the regenerative oral phenotype, leading to faster healing and less severe scarring.
GAS6 and AXL were also less active in facial and oral scars from repetitive injuries in five volunteers, showing that this axis is conserved in humans. “… we hypothesized that in cases of aberrant wound healing, such as after repetitive injury, the fibrotic program “overcomes” the antifibrotic potential of GAS6-AXL, resulting in decreased expression and use of this pathway, increased expression of FAK, and scarring in the typically nonscarring tissue,” they wrote. Tests in mice then showed that activating AXL by exogenous GAS6 in repetitively injured mouse oral tissue resulted in better wound healing outcomes and reduced scarring.”
The authors acknowledged that the mechanisms through which AXL drives regeneration are not yet clear, and further studies will be needed to examine the molecular mechanism underlying the specific mechanism by which AXL suppresses FAK. Nevertheless, they point out, their study represents a first step in understanding what drives regeneration versus fibrosis.
“Unfortunately, current treatments do not adequately resolve or prevent scarring because we do not fully understand the mechanism,” Klein said. “Our research helps fill in that knowledge gap…This data shows that the GAS6-AXL pathway is potentially important for scarless healing in the mouth and that manipulating it may help reduce skin scars as well.
The authors further concluded, “In summary, our results provide a comprehensive transcriptomic characterization of regenerative wound repair in the oral mucosa, highlighting how GAS6-AXL signaling may lead to scarless healing in the oral mucosa… Activation of AXL through GAS6 application could rescue the regenerative phenotype of repetitively injured oral mucosa and reduce skin scarring. Thus, the GAS6-AXL pathway is a potential therapeutic target for oral mucosa and skin scarring.”
The next steps are to further determine how these preclinical findings apply to humans and to develop therapies to improve healing of skin wounds, according to Michael Longaker, MD, the Dean P. and Louise Mitchell Professor in the School of Medicine at Stanford University, and the study’s co-corresponding author. “Further clinical studies should be performed to assess the nature of the relationship between AXL and scarring in humans,” Longaker said.
The post Secrets of Rapid Scarless Mouth Healing Uncovered via scRNA-Seq appeared first on GEN - Genetic Engineering and Biotechnology News.
In the oral mucosa they found a signaling pathway between cells, involving a protein called GAS6 and an enzyme called AXL, which blocks a different cellular pathway, known as FAK, that promotes scarring. When the investigators inhibited the AXL enzyme in the laboratory mice, the oral mucosa wounds’ healing worsened, making them more like skin wounds. When AXL was stimulated in the skin wounds, they healed much like oral mucosa wounds, regenerating tissue more efficiently.
The results hint at a strategy that could help to limit fibrosis and scarring in injuries outside of the mouth. If confirmed in humans, the findings could one day lead to treatments that enable rapid, scarless recovery from skin wounds on different parts of the body.
The team, co-led by Ophir Klein, MD, PhD, executive vice dean of Children’s Health at Cedars-Sinai, executive director of Cedars-Sinai Guerin Children’s, the David and Meredith Kaplan Distinguished Chair in Children’s Health, reported on their findings in Science Translational Medicine, in a paper titled “Growth arrest specific–6 and angiotoxin receptor–like signaling drive oral regenerative wound repair.” In their paper the team stated, “Our demonstration that AXL and FAK expression act as indicators of regeneration versus fibrosis, respectively, lends our study therapeutic potential.”
Human skin can repair itself after injuries, but not without producing scar tissue. These scars can diminish the long-term function of the skin, and scars on areas such as the face can also be an aesthetic concern for patients. Currently, there aren’t any treatments that can prevent facial scarring or erase scars after they’ve formed. “The main barrier to the development of effective scarring treatments is our limited understanding of the molecular mechanisms underpinning scar formation and the mechanisms that govern repair without scarring,” the authors explained.
Searching for scar-preventing therapies, Klein and colleagues took inspiration from the oral mucosa. The oral mucosa repairs wounds faster and more efficiently than any other barrier site in the adult mammalian body and can heal without scarring in just one to three days, the authors further noted. “Oral wounds heal at nearly three times the rate of matched dermal wounds, exhibiting a much lower inflammatory response and reduced or no scarring,” they stated. But despite this “remarkable regenerative capacity of the oral mucosa,” the cellular and molecular mechanisms that regulate this rapid regeneration aren’t clear. “Our research began with two questions: Why does your mouth heal so much better than your skin?” said Klein, “[…] And if we figure that out, can we use that information therapeutically?”
To uncover the secrets of wound-healing in the oral mucosa, the team compared mouse oral mucosal fibroblasts (OMFs) to facial skin fibroblasts (FAFs), across the time course of wound healing. They found that the oral mucosal fibroblasts suppressed fibrosis and the enzyme FAK through a signaling pathway involving the protein AXL. Knocking out AXL revived FAK activity and led to scarring after oral injuries in mice.
Conversely, stimulating AXL in wounds on the face using the protein GAS6 skewed wound healing towards the regenerative oral phenotype, leading to faster healing and less severe scarring.
GAS6 and AXL were also less active in facial and oral scars from repetitive injuries in five volunteers, showing that this axis is conserved in humans. “… we hypothesized that in cases of aberrant wound healing, such as after repetitive injury, the fibrotic program “overcomes” the antifibrotic potential of GAS6-AXL, resulting in decreased expression and use of this pathway, increased expression of FAK, and scarring in the typically nonscarring tissue,” they wrote. Tests in mice then showed that activating AXL by exogenous GAS6 in repetitively injured mouse oral tissue resulted in better wound healing outcomes and reduced scarring.”
The authors acknowledged that the mechanisms through which AXL drives regeneration are not yet clear, and further studies will be needed to examine the molecular mechanism underlying the specific mechanism by which AXL suppresses FAK. Nevertheless, they point out, their study represents a first step in understanding what drives regeneration versus fibrosis.
“Unfortunately, current treatments do not adequately resolve or prevent scarring because we do not fully understand the mechanism,” Klein said. “Our research helps fill in that knowledge gap…This data shows that the GAS6-AXL pathway is potentially important for scarless healing in the mouth and that manipulating it may help reduce skin scars as well.
The authors further concluded, “In summary, our results provide a comprehensive transcriptomic characterization of regenerative wound repair in the oral mucosa, highlighting how GAS6-AXL signaling may lead to scarless healing in the oral mucosa… Activation of AXL through GAS6 application could rescue the regenerative phenotype of repetitively injured oral mucosa and reduce skin scarring. Thus, the GAS6-AXL pathway is a potential therapeutic target for oral mucosa and skin scarring.”
The next steps are to further determine how these preclinical findings apply to humans and to develop therapies to improve healing of skin wounds, according to Michael Longaker, MD, the Dean P. and Louise Mitchell Professor in the School of Medicine at Stanford University, and the study’s co-corresponding author. “Further clinical studies should be performed to assess the nature of the relationship between AXL and scarring in humans,” Longaker said.
The post Secrets of Rapid Scarless Mouth Healing Uncovered via scRNA-Seq appeared first on GEN - Genetic Engineering and Biotechnology News.