Inhibition of prolyl 4-hydroxylase reduces scar hypertrophy in a rabbit model of cutaneous scarring

Hypertrophic scars result from excessive collagen deposition at sights of healing dermal wounds and can be functionally and cosmetically problematic. Pharmacological regulation of collagen synthesis and deposition is a direct approach to the control of scar tissue formation. We tested the ability of the phenanthrolinone derivative FG-1648 (in 0.5% Carbopol 971 PNF gel, pH 6.5), a prolyl 4-hydroxylase inhibitor, to reduce hypertrophic scar formation in a rabbit ear hypertrophic scar model. New Zealand White rabbits were divided into two treatment groups (n = 12 wounds per group with an equal number of controls): low-dose group: 0.5% FG-1648; high-dose group: 1% FG-1648. Left ears were used for treatment and right ear for control. Four 7-mm dermal ulcer wounds were made on each ear. The inhibitor was topically applied to the wound at the time of wounding and once daily up to postoperative day 7. Wounds were harvested at postoperative day 28 and scar hypertrophy quantified by measurement of the scar elevation index. All wounds showed complete healing. Treatment of wounds with 1% prolyl 4-hydroxylase inhibitor decreased the scar elevation index by 26% compared to control wounds (p < 0.01). Wounds treated with 0.5% FG-1648 inhibitor showed no difference in scar elevation compared to control wounds. These results suggest that inhibition of prolyl 4-hydroxylase may be a suitable agent for topical treatment for the prevention of hypertrophic scar tissue.     

Endotoxin‐induced inflammation in a rodent model up‐regulates IL‐1a expression and CD45+ leukocyte recruitment and increases the rate of reepithelialization and wound closure

Wound healing is traditionally divided into inflammation, proliferation, and remodeling phases. Several inflammatory mediators and cells regulate the inflammation phase. The specific roles for different mediators have not been clearly defined. The effects of inflammation phase modulation on wound healing were evaluated in this study. Rat full‐thickness wounds were divided into different experimental groups: (1) sterile hyper‐inflammatory wounds/endotoxin (topical endotoxin), (2) sterile hypo‐inflammatory/inhibitor group (cocktail of topical COX‐1 plus COX‐2 plus lipoxygenase inhibitors), and (3) control groups: topical saline or DMSO. After full‐thickness wound creation, custom‐made titanium chambers enclosed the wound, creating an isolated well‐controlled environment. Wound healing was followed over time; tissue biopsies and wound fluid samples were collected on days 1, 4, and 8 postoperatively. The validity of the inflammation model was confirmed by increased IL‐1a expression, increased CD45+ leukocytes recruitment in the hyper‐inflamed group as compared to the inhibitor and control groups. The reepithelialization percentage was significantly increased in the endotoxin group as compared to the inhibitor group on day 4 (60.75 vs. 22.05, p‐value <0.05) and both the inhibitor and the control group on day 8 (control group: 63.2%, inhibitor group: 28.9%, endotoxin group: 84.2%, p‐value <0.05). Also, the macroscopic wound closure was increased in the endotoxin group as compared to the inhibitor group and control group both on day 4 (control group: 69.9%, inhibitor group: 62.9%, endotoxin group: 81.9%, p‐value <0.05) and on day 8 (control group: 68.5%, inhibitor group: 69.1%, endotoxin group: 83.7%, p‐value <0.05). Endotoxin‐induced sterile inflammation up‐regulates IL‐1a expression and CD45+ leukocyte recruitment and results in faster rate of wound reepithelialization and wound closure in full‐thickness rodent wounds. Conversely, the wound reepithelialization and wound closure can be significantly delayed on treatment with a combination of cyclooxygenase and lipoxygenase inhibitors.     

Wound healing in a fetal,adult, and scar tissue model: A comparative study

Early gestation fetal wounds heal without scar formation. Understanding the mechanism of this scarless healing may lead to new therapeutic strategies for improving adult wound healing. The aims of this study were to develop a human fetal wound model in which fetal healing can be studied and to compare this model with a human adult and scar tissue model. A burn wound (10 × 2 mm) was made in human ex vivo fetal, adult, and scar tissue under controlled and standardized conditions. Subsequently, the skin samples were cultured for 7, 14, and 21 days. Cells in the skin samples maintained their viability during the 21‐day culture period. Already after 7 days, a significantly higher median percentage of wound closure was achieved in the fetal skin model vs. the adult and scar tissue model (74% vs. 28 and 29%, respectively, p<0.05). After 21 days of culture, only fetal wounds were completely reepithelialized. Fibroblasts migrated into the wounded dermis of all three wound models during culture, but more fibroblasts were present earlier in the wound area of the fetal skin model. The fast reepithelialization and prompt presence of many fibroblasts in the fetal model suggest that rapid healing might play a role in scarless healing.     

The alarmin HMGB‐1 influences healing outcomes in fetal skin wounds

In mice, cutaneous wounds generated early in development (embryonic day 15, E15) heal scarlessly, while wounds generated late in gestation (embryonic day 18, E18) heal with scar formation. Even though both types of wounds are generated in the same sterile uterine environment, scarless fetal wounds heal without inflammation, but a strong inflammatory response is observed in scar‐forming fetal wounds. We hypothesized that altered release of alarmins, endogenous molecules that trigger inflammation in response to damage, may be responsible for the age‐related changes in inflammation and healing outcomes in fetal skin. The purpose of this study was to determine whether the alarmin high‐mobility group box‐1 (HMGB‐1) is involved in fetal wound repair. Immunohistochemical analysis showed that in unwounded skin, E18 keratinocytes expressed higher levels of HMGB‐1 compared with E15 keratinocytes. After injury, HMGB‐1 was released to a greater extent from keratinocytes at the margin of scar‐forming E18 wounds, compared with scarless E15 wounds. Furthermore, instead of healing scarlessly, E15 wounds healed with scars when treated with HMGB‐1. HMGB‐1‐injected wounds also had more fibroblasts, blood vessels, and macrophages compared with control wounds. Together, these data suggest that extracellular HMGB‐1 levels influence the quality of healing in cutaneous wounds.     

Modulation of the inflammatory response by increasing fetal wound size or interleukin‐10 overexpression determines wound phenotype and scar formation

Wound size impacts the threshold between scarless regeneration and reparative healing in the fetus with increased inflammation showed in fetal scar formation. We hypothesized that increased fetal wound size increases pro‐inflammatory and fibrotic genes with resultant inflammation and fibroplasia and that transition to scar formation could be reversed by overexpression of interleukin‐10 (IL‐10). To test this hypothesis, 2‐mm and 8‐mm dermal wounds were created in mid‐gestation fetal sheep. A subset of 8‐mm wounds were injected with a lentiviral vector containing the IL‐10 transgene (n = 4) or vehicle (n = 4). Wounds were harvested at 3 or 30 days for histology, immunohistochemistry, analysis of gene expression by microarray, and validation with real‐time polymerase chain reaction. In contrast to the scarless 2‐mm wounds, 8‐mm wounds showed scar formation with a differential gene expression profile, increased inflammatory cytokines, decreased CD45+ cells, and subsequent inflammation. Lentiviral‐mediated overexpression of the IL‐10 gene resulted in conversion to a regenerative phenotype with decreased inflammatory cytokines and regeneration of dermal architecture. In conclusion, increased fetal wounds size leads to a unique gene expression profile that promotes inflammation and leads to scar formation and furthermore, these results show the significance of attenuated inflammation and IL‐10 in the transition from fibroplasia to fetal regenerative healing.     

Interleukin‐33 encourages scar formation in murine fetal skin wounds

The magnitude of the inflammatory response after skin injury is important for determining whether wounds in developing fetal skin will heal scarlessly (minimal inflammation) or with prominent scars (robust inflammation). One class of inflammatory mediators gaining attention for their role in wound inflammation is alarmins. In the current study, the alarmin interleukin‐33 (IL‐33) was examined in a mouse model of fetal wound healing. IL‐33 expression was elevated in scar‐forming embryonic day 18 wounds compared to scarless embryonic day 15 wounds. Furthermore, injection of IL‐33 into embryonic day 15 wounds caused scarring when wounds were analyzed at 7 days postwounding. The introduction of IL‐33 into embryonic day 15 wounds did not induce statistically significant changes in the number of neutrophils, mast cells, or macrophages in vivo. However, IL‐33 treatment enhanced collagen expression in cultured fibroblasts derived from adult and fetal murine skin, suggesting that IL‐33 may directly stimulate fibroblasts. In vitro studies suggested that the stimulation of collagen production by IL‐33 in fibroblasts was partially dependent on NF‐κB activation. Overall, the data suggest an association between IL‐33 and scar formation in fetal wounds.     

Novel differences in the expression of inflammation‐associated genes between mid‐ and late‐gestational dermal fibroblasts

While cutaneous wounds of late‐gestational fetuses and on through adulthood result in scar formation, wounds incurred early in gestation have been shown to heal scarlessly. Unique properties of fetal fibroblasts are believed to mediate this scarless healing process. In this study, microarray analysis was used to identify differences in the gene expression profiles of cultured fibroblasts from embryonic day 15 (E15; midgestation) and embryonic day 18 (E18; late‐gestation) skin. Sixty‐two genes were differentially expressed and 12 of those genes are associated with inflammation, a process that correlates with scar formation in fetal wounds. One of the differentially expressed inflammatory genes was cyclooxygenase‐1 (COX‐1). COX‐1 was more highly expressed in E18 fibroblasts than in E15 fibroblasts, and these differences were confirmed at the gene and protein level. Differences in COX‐1 protein expression were also observed in fetal skin by immunohistochemical and immunofluorescence staining. The baseline differences in gene expression found in mid‐ and late‐gestational fetal fibroblasts suggest that developmental alterations in fibroblasts could be involved in the transition from scarless to fibrotic fetal wound healing. Furthermore, baseline differences in the expression of inflammatory genes by fibroblasts in E15 and E18 skin may contribute to inflammation and scar formation late in gestation.     

The Effectiveness of the Haemodialysate Solcoseryl® for Second‐Intention Wound Healing in Horses and Ponies

Second‐intention healing of limb wounds in horses is often problematic. Solcoseryl^® is a protein‐free, standardized dialysate/ultrafiltrate (HD) derived from calf blood, which has been shown to improve healing in both animals and humans. The efficacy of HD in the healing of deep wounds in horses and ponies was investigated. Deep wounds of 20 by 35 mm were created on both metatarsi (skin, subcutis, periosteum) and on both femoral biceps muscles (skin, subcutis, muscle) of five horses and five ponies. The wounds on one side were treated with HD, four times a week during the period that the wounds were bandaged and once daily thereafter. The wounds on the other side were left untreated. In the first 4 weeks of the healing period HD stimulated healing but inhibited healing thereafter. This pattern was significant for all wound groups (P < 0.001). Because of this change in effect, the overall effect on wound healing over the entire period was not significant (P = 0.77). HD stimulated healing initially by provoking a greater initial inflammatory response, faster contraction and faster formation of granulation tissue. Subsequently, HD inhibited healing because it significantly delayed epithelialization and caused protracted inflammation. The effects of HD were most pronounced in the horses. Because this study distinguished between contraction and epithelialization, it could be shown that HD stimulated contraction but inhibited epithelialization. Therefore, HD is useful in horses for the treatment of deep wounds during the initial phase of healing by second intention, i.e. during the first weeks when wound contraction can be expected. Treatment should be ceased when epithelialization becomes predominant.     

Stimulation of cutaneous wound healing by an FPR2‐specific peptide agonist WKYMVm

Diabetes is one of the most common human diseases and 15% of the 200 million diabetics worldwide suffer from diabetic wounds. Development of new therapeutic agents is needed for treatment of diabetic wounds. Wound healing is mediated by multiple steps, including inflammation, epithelialization, neoangiogenesis, and granulation. Formyl peptide receptor 2 has been known to stimulate angiogenesis, which is essential for tissue repair and cutaneous wound healing. In this study, we explored the therapeutic effects of WKYMVm (Trp‐Lys‐Tyr‐Met‐Val‐D‐Met‐NH2), a synthetic peptide agonist of formyl peptide receptor 2, on cutaneous wounds in streptozotocin‐induced diabetic rats. Topical application of WKYMVm onto cutaneous wounds stimulated formation of von Willebrand factor‐positive capillary and α‐smooth muscle actin‐positive arteriole with a maximal stimulation on day 6, suggesting WKYMVm‐stimulated angiogenesis. Infiltration of immune cells could be detected on early phase during wound healing and WKYMVm treatment acutely augmented infiltration of CD68‐positive macrophages. In addition, reepithelialization and granulation tissue formation were accelerated by treatment with WKYMVm. These results suggest that WKYMVm has therapeutic effects on diabetic wounds by stimulating angiogenesis and infiltration of immune cells.     

Anti‐inflammatory effects of haptoglobin on LPS‐stimulated macrophages: Role of HMGB1 signaling and implications in chronic wound healing

Nonhealing wounds possess elevated numbers of pro‐inflammatory M1 macrophages, which fail to transition to anti‐inflammatory M2 phenotypes that promote healing. Hemoglobin (Hb) and haptoglobin (Hp) proteins, when complexed (Hb‐Hp), can elicit M2‐like macrophages through the heme oxygenase‐1 (HO‐1) pathway. Despite the fact that nonhealing wounds are chronically inflamed, previous studies have focused on non‐inflammatory systems, and do not thoroughly compare the effects of complexed vs individual proteins. We aimed to investigate the effect of Hb/Hp treatments on macrophage phenotype in an inflammatory, lipopolysaccharide (LPS)‐stimulated environment, similar to chronic wounds. Human M1 macrophages were cultured in vitro and stimulated with LPS. Concurrently, Hp, Hb, or Hb‐Hp complexes were delivered. The next day, 27 proteins related to inflammation were measured in the supernatants. Hp treatment decreased a majority of inflammatory factors, Hb increased many, and Hb‐Hp had intermediate trends, indicating that Hp attenuated overall inflammation to the greatest extent. From this data, Ingenuity Pathway Analysis software identified high motility group box 1 (HMGB1) as a key canonical pathway—strongly down‐regulated from Hp, strongly up‐regulated from Hb, and slightly activated from Hb‐Hp. HMGB1 measurements in macrophage supernatants confirmed this trend. In vivo results in diabetic mice with biopsy punch wounds demonstrated accelerated wound closure with Hp treatment, and delayed wound closure with Hb treatment. This work specifically studied Hb/Hp effects on macrophages in a highly inflammatory environment relevant to chronic wound healing. Results show that Hp—and not Hb‐Hp, which is known to be superior in noninflammatory conditions—reduces inflammation in LPS‐stimulated macrophages, and HMGB1 signaling is also implicated. Overall, Hp treatment on M1 macrophages in vitro reduced the inflammatory secretion profile, and also exhibited benefits in in silico and in vivo wound‐healing models.     

The role of allogenic keratin‐derived dressing in wound healing in a mouse model

Keratin is an interesting protein needed for wound healing and tissue recovery. We have recently proposed a new, simple and inexpensive method to obtain fur and hair keratin‐derived biomaterials suitable for medical application. The aim of the study was to evaluate the role of the fur keratin‐derived protein (FKDP) dressing in the allogenic full‐thickness surgical skin wound model. The data obtained using scanning electron microscopy showed that employed processed biomaterial had higher surface porosity compared with control raw material. From the MTS test, it was found keratin biomaterial is not only toxic to the NIH/3T3 cell line (p < 0.05), but also enhances cell proliferation compared with the control. In vivo studies have shown keratin dressings are tissue biocompatible, accelerate wound closure and epithelialization to the statistically significant differences on day 5 (p < 0.05) in comparison to control wounds. Histological examination revealed, that in FKDP‐treated wounds the inflammatory response contained predominantly macrophages whilst their morphological untreated variants showed mixed cell infiltrates rich in neutrophils. Predominant macrophages based response creates more favorable environment for healing. In FKDP‐dressed wounds the number of microhemorrhages was also significantly decreased (p < 0.05) as compared with undressed wounds. Applied keratin dressing favors reconstruction of a more regular skin structure and assures better cosmetic effect in terms of scar formation and appearance. In conclusion, fur keratin‐derived protein dressings significantly accelerated wound healing in the mouse model. Further studies are needed to determine the molecular mechanisms involved in the multilayer wound healing process and to assess the possible use of these dressings for medical purposes.     

Embryonic stem cell–derived M2‐like macrophages delay cutaneous wound healing

In adults, repair of deeply injured skin wounds results in the formation of scar tissue, whereas in embryos wounds heal almost scar‐free. Macrophages are important mediators of wound healing and secrete cytokines and tissue remodeling enzymes. In contrast to host defense mediated by inflammatory M1 macrophages, wound healing and tissue repair involve regulatory M2/M2‐like macrophages. Embryonic/fetal macrophages are M2‐like, and this may promote scar‐free wound healing. In the present study, we asked whether atopical application of ex vivo generated, embryonic stem cell–derived macrophages (ESDM) improve wound healing in mice. ESDM were tested side by side with bone marrow–derived macrophages (BMDM). Compared to BMDM, ESDM resembled a less inflammatory and more M2‐like macrophage subtype as indicated by their reduced responsiveness to lipopolysaccharide, reduced expression of Toll‐like receptors, and reduced bacterial phagocytosis. Despite this anti‐inflammatory phenotype in cell culture, ESDM prolonged the healing of deep skin wounds even more than BMDM. Healed wounds had more scar formation compared to wounds receiving BMDM or cell‐free treatment. Our data indicate that atopical application of ex vivo generated macrophages is not a suitable cell therapy of dermal wounds.     

The beneficial effect of traditional Japanese herbal (Kampo) medicine,Hochu‐ekki‐to (Bu‐Zhong‐Yi‐Qi‐Tang), for patients with chronic wounds refractory to conventional therapies: A prospective,randomized trial

Hochu‐ekki‐to (HET) is a traditional Japanese herbal (Kampo) medicine for the treatment of severe weakness, loss of appetite, and indigestion in elderly patients and for the prevention of opportunistic infections. The impact of HET on patients with chronic wounds refractory to conventional therapies was investigated in a prospective, randomized trial, including 18 patients divided into medication (7.5 g oral HET per day, n = 9) and control (n = 9) groups. Wound healing during the 12‐week study period was scored based on depth, exudate, size, inflammation/infection, granulation tissue, necrotic tissue, and pocket size. At 12 weeks, wound healing progressed in all nine patients in the medication group, whereas wound healing progressed in only three patients in the control group (significant difference, p < 0.01; relative risk: 3.00). In the medication group, the total score decreased significantly at 8 weeks and later. To the best of our knowledge, this study was the first to show that HET promoted the healing of chronic wounds resistant to conventional treatments. HET may be a choice as an adjunctive therapy for chronic wounds, particularly for patients with malnutrition. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000031620).     

Comparative study of wound healing in rat skin following incision with a novel picosecond infrared laser (PIRL) and different surgical modalities

Background and Objective

As a result of wound healing the original tissue is replaced by dysfunctional scar tissue. Reduced tissue damage during surgical procedures beneficially affects the size of the resulting scar and overall healing time. Thus the choice of a particular surgical instrument can have a significant influence on the postoperative wound healing. To overcome these problems of wound healing we applied a novel picosecond infrared laser (PIRL) system to surgical incisions. Previous studies indicated that negligible thermal, acoustic, or ionization stress effects to the surrounding tissue results in a superior wound healing.

Study Design/Materials and Methods

Using the PIRL system as a surgical scalpel, we performed a prospective wound healing study on rat skin and assessed its final impact on scar formation compared to the electrosurgical device and cold steel. As for the incisions, 6 full‐thickness, 1‐cm long‐linear skin wounds were created on the dorsum of four rats using the PIRL, an electrosurgical device, and a conventional surgical scalpel, respectively. Rats were euthanized after 21 days of wound healing. The thickness of the subepithelial fibrosis, the depth and the transverse section of the total scar area of each wound were analyzed histologically.

Results

After 21 days of wound healing the incisions made by PIRL showed minor scar tissue formation as compared to the electrosurgical device and the scalpel. Highly significant differences (P < 0.001) were noted by comparing the electrosurgical device with PIRL and scalpel. The transverse section of the scar area also showed significant differences (P = 0.043) when comparing PIRL (mean: 141.46 mm²; 95%CI: 105.8–189.0 mm²) with scalpel incisions (mean: 206.82 mm²; 95%CI: 154.8–276.32 mm²). The subepithelial width of the scars that resulted from using the scalpel were 1.3 times larger than those obtained by using the PIRL (95%CI: 1.0–1.6) though the difference was not significant (P < 0.083).

Conclusions

The hypothesis that PIRL results in minimal scar formation with improved cosmetic outcomes was positively verified. In particular the resection of skin tumors or pathological scars, such as hypertrophic scars or keloids, are promising future fields of PIRL application. Lasers Surg. Med. 48:385–391, 2016. © 2016 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.     

Avocado/soybean unsaponifiables: a novel regulator of cutaneous wound healing,modelling and remodelling

We investigated the effects of avocado/soybean unsaponifiables (ASU) on the healing response of cutaneous wound defect in rats. Sixty male rats were randomly divided into three groups including control, vehicle and treatment (n = 20 in each group). A 2 × 2 cm² wound defect was made on the dorsum. The control, vehicle and treatment groups were treated daily with topical application of saline, cream and cream/ASU for 10 days, respectively. The wounds were monitored daily. The animals were euthanised at 10, 20 and 30 days post injury (D). The dry matter, hydroxyproline, collagen, n‐acetyl glucosamine (NAGLA) and n‐acetyl galactosamine (NAGAA) contents of the skin samples were measured and the histopathological and biomechanical characteristics of the samples were investigated. Statistics of P < 0·05 was considered significant. Treatment significantly increased tissue glycosaminoglycans and collagen contents at various stages of wound healing compared to controls. Treatment modulated inflammation, improved fibroplasia and produced high amounts of scar tissue at short term. At long term, treatment reduced the scar tissue size and increased the quality and rate of wound contraction and reepithelisation compared to controls. The treated lesions were more cosmetically pleasing and had significantly higher biomechanical characteristics than controls. ASU was effective in rat wound healing.     

Orf virus IL‐10 accelerates wound healing while limiting inflammation and scarring

Interleukin (IL)‐10 plays a critical role in controlling wound inflammation and scar formation. Orf virus, a zoonotic parapoxvirus, induces proliferative skin lesions that resolve with minimal scarring. Orf virus encodes a range of factors that subvert the host's response to infection, including a homolog of IL‐10. This study investigated, using a murine full‐thickness wound model, whether purified orf virus IL‐10 (ovIL‐10) can regulate skin repair and scarring. Repeat injections of ovIL‐10 into wounded skin accelerated wound closure. Histological analyses of wound sections revealed that treatment with ovIL‐10 accelerated wound reepithelialization, granulation tissue coverage of the wound bed, and improved wound revascularization. In addition, wounds treated with ovIL‐10 showed a reduction in macrophage infiltration, myofibroblast differentiation, and wound contraction. Treatment of wounds with ovIL‐10 also resulted in a reduction in visible scarring that was consistent with the extent of scar tissue formed. Quantitative polymerase chain reaction analysis confirmed that ovIL‐10 reduced the expression of key mediators of inflammation and granulation tissue formation. These findings show that ovIL‐10, like mammalian IL‐10, limits inflammation and scar tissue formation and reveal a new role for both mammalian and viral IL‐10 in mediating tissue repair.     

Reduction of scar formation in full-thickness wounds with topical celecoxib treatment

Adult wound repair occurs with an initial inflammatory response, reepithelialization, and the formation of a permanent scar. Although the inflammatory phase is often considered a necessity for successful adult wound healing, fetal healing studies have shown the ability to regenerate skin and to heal wounds in a scarless manner in the absence of inflammation. The cyclooxygenase-2 (COX-2) enzyme, a known mediator of inflammation, has been shown to contribute to a variety of inflammatory conditions and to the development of cancer in many organs. To examine the role of COX-2 in the wound healing process, incisional wounds were treated topically with the anti-inflammatory COX-2 inhibitor celecoxib. Acutely, celecoxib inhibited several parameters of inflammation in the wound site. This decrease in the early inflammatory phase of wound healing had a significant effect on later events in the wound healing process, namely a reduction in scar tissue formation, without disrupting reepithelialization or decreasing tensile strength. Our data suggest that in the absence of infection, adult wound healing is able to commence with decreased inflammation and that anti-inflammatory drugs may be used to improve the outcome of the repair process in the skin by limiting scar formation.     

Transgenic mice overexpressing CD109 in the epidermis display decreased inflammation and granulation tissue and improved collagen architecture during wound healing

Transforming growth factor‐β (TGF‐β) is a multifunctional growth factor involved in all aspects of wound healing. TGF‐β accelerates wound healing, but an excess of its presence at the wound site has been implicated in pathological scar formation. Our group has recently identified CD109, a glycophosphatidylinositol‐anchored protein, as a novel TGF‐β coreceptor and inhibitor of TGF‐β signaling in vitro. To determine the effects of CD109 in vivo on wound healing, we generated transgenic mice overexpressing CD109 in the epidermis. In excisional wounds, we show that CD109 transgenic mice display markedly reduced macrophage and neutrophil recruitment, granulation tissue area, and decreased Smad2 and Smad3 phosphorylation, whereas wound closure remains unaffected as compared with wild‐type littermates. Futhermore, we demonstrate that the expression of the proinflammatory cytokines interleukin‐1α and monocyte chemoattractant protein‐1, and extracellular matrix components is markedly decreased during wound healing in CD109 transgenic mice. In incisional wounds, CD109 transgenic mice show improved dermal architecture, whereas the tensile strength of the wound remains unchanged. Taken together, our findings demonstrate that CD109 overexpression in the epidermis reduces inflammation and granulation tissue area and improves collagen organization in vivo.