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

João Moura, Anja Sørensen, Ermelindo C. Leal, Rikke Svendsen, Lina Carvalho, Rie Juul Willemoes, Per Trolle Jørgensen, Håvard Jenssen, Jesper Wengel, Louise Torp Dalgaard, Eugénia Carvalho*

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article number5836
JournalScientific Reports
Volume9
Number of pages11
ISSN2045-2322
DOIs
Publication statusPublished - 9. Apr 2019

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Fibroblast Growth Factor 7
MicroRNAs
Skin
Wounds and Injuries
Diabetic Foot
Keratinocytes
Proteins
Messenger RNA

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Moura, J., Sørensen, A., Leal, E. C., Svendsen, R., Carvalho, L., Willemoes, R. J., ... Carvalho, E. (2019). microRNA-155 inhibition restores Fibroblast Growth Factor 7 expression in diabetic skin and decreases wound inflammation. Scientific Reports, 9, [5836]. https://doi.org/10.1038/s41598-019-42309-4
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. / microRNA-155 inhibition restores Fibroblast Growth Factor 7 expression in diabetic skin and decreases wound inflammation. In: Scientific Reports. 2019 ; Vol. 9.
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abstract = "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.",
author = "Jo{\~a}o Moura and Anja S{\o}rensen and Leal, {Ermelindo C.} and Rikke Svendsen and Lina Carvalho and Willemoes, {Rie Juul} and J{\o}rgensen, {Per Trolle} and H{\aa}vard Jenssen and Jesper Wengel and Dalgaard, {Louise Torp} and Eug{\'e}nia Carvalho",
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Moura, J, Sørensen, A, Leal, EC, Svendsen, R, Carvalho, L, Willemoes, RJ, Jørgensen, PT, Jenssen, H, Wengel, J, Dalgaard, LT & Carvalho, E 2019, 'microRNA-155 inhibition restores Fibroblast Growth Factor 7 expression in diabetic skin and decreases wound inflammation', Scientific Reports, vol. 9, 5836. https://doi.org/10.1038/s41598-019-42309-4

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

In: Scientific Reports, Vol. 9, 5836, 09.04.2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - microRNA-155 inhibition restores Fibroblast Growth Factor 7 expression in diabetic skin and decreases wound inflammation

AU - Moura, João

AU - Sørensen, Anja

AU - Leal, Ermelindo C.

AU - Svendsen, Rikke

AU - Carvalho, Lina

AU - Willemoes, Rie Juul

AU - Jørgensen, Per Trolle

AU - Jenssen, Håvard

AU - Wengel, Jesper

AU - Dalgaard, Louise Torp

AU - Carvalho, Eugénia

PY - 2019/4/9

Y1 - 2019/4/9

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-019-42309-4

DO - 10.1038/s41598-019-42309-4

M3 - Journal article

C2 - 30967591

AN - SCOPUS:85064080390

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 5836

ER -