Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Sushant Bhattacharya, Rangoli Aggarwal, Vijay Pal Singh, Srinivasan Ramachandran, Malabika Datta

Delayed wound healing is a major complication associated with diabetes and is a result of a complex interplay among diverse deregulated cellular parameters. Although several genes and pathways have been identified to be mediating impaired wound closure, the role of miRNAs in these events is not very well understood. Here, we identify an altered miRNA signature in the prolonged inflammatory phase in a wound during diabetes with increased infiltration of inflammatory cells in the basal layer of the epidermis. Nineteen miRNAs were down-regulated in these diabetic rat wounds (as compared to normal rat wound, Day 7 post-wounding) together with inhibited levels of the central miRNA biosynthesis enzyme, Dicer suggesting that in wounds of diabetic rats, the decreased levels of Dicer are presumably responsible for miRNA down-regulation. As compared to unwounded skin, Dicer levels were significantly up-regulated at 12-days post wounding in normal rats and this was notably absent in diabetic rats that showed impaired wound closure. In a wound healing specific RT-PCR array, ten genes were significantly altered in the diabetic rat wound that majorly included growth factors and collagens. Network analyses demonstrated significant interactions and correlations between the miRNA predicted targets (regulators) and the ten wound healing specific genes suggesting altered miRNAs might fine-tune the levels of these genes that determine wound closure. Dicer inhibition prevented HaCaT cell migration and affected wound closure. Altered levels of Dicer and miRNAs are critical during delayed wound closure and offer promising targets to address the issue of impaired wound healing.