Comparison of microRNAome of human normal and chronic wounds reveals microRNA-17w92 is critical for wound repair
Mi Q, Zhou L. Comparison of microRNAome of human normal and chronic wounds reveals microRNA-17w92 is critical for wound repair. J Invest Deramtol 2017; 137(10 Suppl 2):S306.
J Invest Deramtol
Excessive and prolonged inflammation impedes wound healing (WH) and is characteristic for chronic wounds (CWs). As important gene regulators, microRNAs (miR) hold great therapeutic potentials, but their role in human skin WH remains largely unexplored. To develop miR-based wound treatment, we generated the first miRNAome map of human normal and chronic wounds by RNA-seq of wound-edge tissues from healthy donors and CW patients. A functional screening to unravel the effect of miRs on wound inflammation was followed, using a library of inhibitors targeting the 61 individual miRNAs regulated during normal healing but with aberrant expression in CWs, which identified miR-17∼92 cluster as a critical suppressor of inflammatory responses of epidermal keratinocytes. Using mice lines with keratinocyte-specific knockout of the miR-17∼92 cluster as well as injection of inhibitors of miR-17∼92 cluster members into the wound-edges of wild-type mice, we demonstrated that miR-17∼92 played a central role in restricting keratinocyte inflammatory response and was indispensable for WH, especially under diabetic milieu. Meanwhile, lower miR-17∼92 expression was found in wound-edge keratinocytes of human diabetic and venous ulcers compared to normal wounds. Importantly, local delivery of miR-19b and miR- 20a to the wounds of diabetic mice effectively accelerated WH, suggesting their therapeutic potential. Mechanistically, the expression of miR-19a/b and miR-20a in keratinocytes is upregulated by PDGF-BB. These miRNAs inhibit inflammation through coordinated regulation of TLR3-signalling pathway: miR-19a/b suppressed ERK and NF-κB activation through targeting SHCBP1, while miR-20a decreased ERK, NF-κB and p38 activity by targeting SEMA7A. We anticipate the miR profiles of human wounds will guide future study of miRNAs in WH. Moreover, as a negative regulator of wound inflammation, miR-17∼92 has clear implications for CW pathogenesis and therapy.
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