Bristol, UK. New research shows that by suppressing one of the genes that normally switches on in wound cells, the wounds can heal faster and with reduced scarring. When skin is damaged, whether by accident or surgery, a blood clot forms and cells underneath the wound start to repair the damage, leading to scarring. Scientists and medical care practitioners have worked to alleviate this problem, but problems remain, not just for wound victims but also for people with organ tissue damage through illness or abdominal surgery.

 

Tissue damage triggers an inflammatory response by white cells to protect skin from infection by killing microbes. The same white cells guide the production of layers of collagen. These layers of collagen help the wound heal but they stand out from the surrounding skin and result in scarring.

 

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Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. Ryoichi Mori, Tanya J. Shaw, and Paul Martin. The Journal of Experimental Medicine, Jan 2008; 205: 43 - 51. doi:10.1084/jem.20071412.

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Treating skin wounds (blue) with osteopontin antisense DNA (top) reduces the size of scars (area between arrows).

 

Image courtesy of the University of Bristol.

 

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Scarring is a natural part of tissue repair and is most obvious where skin has healed after a cut or burn. It ranges from trivial (a grazed knee) to chronic (diabetic leg ulcers) and is not limited to the skin. All tissues scar as they repair. For example, alcohol-induced liver damage leads to fibrosis and liver failure, and after most abdominal surgeries scars can often lead to major complications.

 

Research findings by Professor Paul Martin and colleagues at the University of Bristol have major implications for scar-free healing. Osteopontin (OPN) is one of the genes that triggers scarring. Applying a gel to the wound that suppresses OPN can accelerate healing and reduce scarring. It does this in part by increasing the regeneration of blood vessels around the wound and speeding up tissue reconstruction. The findings appear in the Journal of Experimental Medicine.

 

Speaking of the discovery, Professor Martin said "White blood cells (macrophages), and the chemical signals (PDGF) delivered to the wound cells, and osteopontin itself are now all clear targets for developing medicines to improve healing of skin wounds and other organs where fibrotic tissue repair can be debilitating."

 

"We hope that it won’t be too long before such therapies are available in the clinic. Indeed, the technique for suppressing OPN to reduce scarring is currently being licensed and patented by a Biotech company specializing in wound-healing therapies."

 

Earlier research by Professor Martin’s lab and others has shown that embryos of many species, including humans, heal wounds without leaving a scar. Now it looks like the same may be true for adults.

 

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Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. Ryoichi Mori, Tanya J. Shaw, and Paul Martin. The Journal of Experimental Medicine, Jan 2008; 205: 43 - 51. doi:10.1084/jem.20071412.

 

Abstract. Previous studies of tissue repair have revealed osteopontin (OPN) to be up-regulated in association with the wound inflammatory response. We hypothesize that OPN may contribute to inflammation-associated fibrosis. In a series of in vitro and in vivo studies, we analyze the effects of blocking OPN expression at the wound, and determine which inflammatory cells, and which paracrine factors from these cells, may be responsible for triggering OPN expression in wound fibroblasts. Delivery of OPN antisense oligodeoxynucleotides into mouse skin wounds by release from Pluronic gel decreases OPN protein levels at the wound and results in accelerated healing and reduced granulation tissue formation and scarring. To identify which leukocytic lineages may be responsible for OPN expression, we cultured fibroblasts in macrophage-, neutrophil-, or mast cell–conditioned media (CM), and found that macrophage- and mast cell–secreted factors, specifically platelet-derived growth factor (PDGF), induced fibroblast OPN expression. Correspondingly, Gleevec, which blocks PDGF receptor signaling, and PDGF-Rβ–neutralizing antibodies, inhibited OPN induction by macrophage-CM. These studies indicate that inflammation-triggered expression of OPN both hinders the rate of repair and contributes to wound fibrosis. Thus, OPN and PDGF are potential targets for therapeutic modulation of skin repair to improve healing rate and quality.

 

 

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