MicroRNAs: Markers and Mediators of Wound Healing in Diabetes

Chronic non-healing foot ulcers are a major complication of diabetes, occurring in 25% of patients within their lifetime. A common feature that underpins poor wound healing in diabetes is inadequate vascularisation due to diabetes-impaired angiogenesis. Currently there are no adequate biomarkers and effective therapies that improve diabetes-impaired healing. The ability to better identify and treat these wounds would reduce the risk of developing co-morbidities such as lower limb amputations. microRNAs (miRNAs) have been indicated to be reliable biomarkers and have been shown to be dysregulated in diabetic wound tissue. However, their utility as predictive biomarkers of poor healing wounds remained to be investigated. Additionally, there is no consensus on the most appropriate quantification method for miRNAs in biological fluids. miRNAs are known to regulate angiogenesis, however whether they could be targeted to improve diabetes-impaired angiogenic responses remained unknown. Wound-healing related miRNAs, miRNA-16, miRNA-21, miRNA-146a, miRNA-200b and miRNA-378a were detectable in rodent plasma and wound fluid and were quantified by the validated extraction co-efficient method. Furthermore, in plasma and wound fluid from individuals with diabetes-related foot ulcers (DRFUs), miRNA expression at the first visit was not associated with future wound healing outcomes but were associated with features of non-healing DRFUs including ischaemia, wound area and HbA1c. We found that miRNA-200b levels were elevated by diabetes and showed that targeted miRNA-200b inhibition improved diabetes-impaired angiogenic responses, augmenting endothelial tubule formation in vitro and promoted blood flow reperfusion in vivo. In conclusion, inhibition of miRNA-200b may pose as a novel therapeutic target to improve diabetes-impaired angiogenesis, however, the use of miRNAs as predictive biomarkers requires further investigation