Fibromodulin and Its Peptide-based Therapy for Cutaneous and Diabetic Wound Healing
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Fibromodulin and Its Peptide-based Therapy for Cutaneous and Diabetic Wound Healing


Scarring and wounds are a significant clinical issue which affects up to 100 million people worldwide. More specifically, as one of the most common and devastating sequelae of uncontrolled diabetes, chronic non-healing diabetic wounds affect an estimated 25% of diabetic patients. Wound healing process is significantly impaired in diabetic patients, including imbalanced production of extracellular matrix components, aberrant cellular infiltration, abnormal fibroblast function, and insufficient angiogenesis. A molecular therapeutic for diabetic wound healing that acts to restore the molecular and cellular processes is needed for successful wound healing. Fibromodulin (FMOD), as a key molecule required for fetal scarless skin repair, can significantly accelerate wound closure, promote angiogenesis, decrease scarring, and improve extracellular matrix organization. Studies have shown FMOD promotes dermal fibroblast migration, myofibroblast differentiation and contraction, which plays an important role in diabetic wound healing process. F06-C40, a FMOD derived peptide acts similar as FMOD protein and is much faster and easier to generate, which can potentially benefit millions of patients. However, the effect of FMOD and its peptide on diabetic wounds remains unknown. In this study, type II diabetic NONcNZO10 mouse model was used to study the effect of FMOD and its peptide in vivo. After full thickness excisional wounds, scar area, capillary formation, and extracellular matrix formation and collagen architecture were determined. In vitro, hyperglycemia-induced fibroblasts and primary human dermal diabetic fibroblasts were treated with FMOD and its derived peptide to study the effect of FMOD and its peptide on diabetic dermal fibroblast proliferation, migration, contraction and invasion. To further investigate the mechanism of FMOD on wound healing in a molecular level, the effect of FMOD on cell adhesion was analyzed and the downstream molecule was studied. In addition, TGF-beta 1 plays an important role in scarring and fibrosis formation. The effect of FMOD on TGF-beta 1 pathway was determined to further elucidate the role of FMOD on wound healing and scar reduction. As a result, FMOD and its peptide successfully accelerated wound closure, reduced scar formation and promoted angiogenesis in vivo. In addition, they promoted diabetic fibroblast migration, contraction and invasion. FMOD promoted fibroblast cell adhesion via integrin. And FMOD shows a down regulation on TGF-beta 1 non-canonical pathway, which is the opposite effect on TGF-beta 1 canonical pathway according to previous studies. Therefore, FMOD and its peptide have the potential to treat diabetic wounds by improving fibroblast characteristics.

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