microRNA-155 inhibition restores Fibroblast Growth Factor 7 expression in diabetic skin and decreases wound inflammation

• Published in: Scientific reports Vol. 9; no. 1; p. 5836
• Main Authors: Moura, João, Sørensen, Anja, Leal, Ermelindo C., Svendsen, Rikke, Carvalho, Lina, Willemoes, Rie Juul, Jørgensen, Per Trolle, Jenssen, Håvard, Wengel, Jesper, Dalgaard, Louise Torp, Carvalho, Eugénia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.04.2019; Nature Publishing Group
• Subjects: 13/106; 14/63; 38/77; 45/61; 59; 64/60; 692/420/254; 692/699/2743/137/138; Animals; Colonization; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetic Foot - metabolism; Feet; Fibroblast growth factor 7; Fibroblast Growth Factor 7 - genetics; Fibroblast Growth Factor 7 - metabolism; Fibroblast growth factor receptor 7; Fibroblasts; Foot diseases; Growth factors; Humanities and Social Sciences; Humans; Inflammation; Keratinocytes - metabolism; Leg ulcers; Male; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; mRNA; multidisciplinary; Re-Epithelialization - physiology; Science; Science (multidisciplinary); Skin; Ulcers; Up-Regulation; Wound healing; Wound Healing - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-42309-4

Treatment for chronic diabetic foot ulcers is limited by the inability to simultaneously address the excessive inflammation and impaired re-epithelization and remodeling. Impaired re-epithelization leads to significantly delayed wound closure and excessive inflammation causes tissue destruction, both enhancing wound pathogen colonization. Among many differentially expressed microRNAs, miR-155 is significantly upregulated and fibroblast growth factor 7 (FGF7) mRNA (target of miR-155) and protein are suppressed in diabetic skin, when compared to controls, leading us to hypothesize that topical miR-155 inhibition would improve diabetic wound healing by restoring FGF7 expression. In vitro inhibition of miR-155 increased human keratinocyte scratch closure and topical inhibition of miR-155 in vivo in wounds increased murine FGF7 protein expression and significantly enhanced diabetic wound healing. Moreover, we show that miR-155 inhibition leads to a reduction in wound inflammation, in accordance with known pro-inflammatory actions of miR-155. Our results demonstrate, for the first time, that topical miR-155 inhibition increases diabetic wound fibroblast growth factor 7 expression in diabetic wounds, which, in turn, increases re-epithelization and, consequently, accelerates wound closure. Topical miR-155 inhibition targets both excessive inflammation and impaired re-epithelization and remodeling, being a potentially new and effective treatment for chronic diabetic foot ulcers.