Abstract
Chronic, non-healing wounds are a significant cause of global morbidity and mortality, and strategies to improve delayed wound closure represent an unmet clinical need. High-density lipoproteins (HDL) can enhance wound healing, but exploitation of this finding is challenging due to the complexity and instability of these heterogeneous lipoproteins. The responsiveness of primary human neonatal keratinocytes, and neonatal and human dermal fibroblasts (HDF) to HDL was confirmed by cholesterol efflux, but promotion of ‘scrape’ wound healing occurred only in primary human neonatal (HDFn) and adult fibroblasts (HDFa). Treatment of human fibroblasts with HDL induced multiple changes in the expression of small non-coding microRNA sequences, determined by microchip array, including hsa-miR-6727-5p. Intriguingly, levels of hsa-miR-6727-5p increased in HDFn, but decreased in HDFa, after exposure to HDL. Delivery of a hsa-miR-6727-5p mimic elicited repression of different target genes in HDFn (ZNF584) and HDFa (EDEM3, KRAS), and promoted wound closure in HDFn. By contrast, a hsa-miR-6727-5p inhibitor promoted wound closure in HDFa. We conclude that HDL treatment exerts distinct effects on the expression of hsa-miR-6727-5p in neonatal and adult fibroblasts, and that this is a sequence which plays differential roles in wound healing in these cell types, but cannot replicate the myriad effects of HDL.
Highlights
Chronic, non-healing wounds are a significant cause of morbidity and mortality in the United Kingdom; according to The Health Improvement Network (THIN database), there were an estimated 3.8 million patients with a wound managed by the National Health Service (NHS) in 2017/2018, of which 89% and 49% of acute and chronic wounds healed, respectively, within the study year [1]
We have investigated the impact of High-density lipoproteins (HDL) on ‘scratch’ wound healing by keratinocytes, neonatal and adult fibroblasts, validated a microchip array screen of selected microRNA sequences altered in human dermal fibroblasts by HDL treatment, and explored the role of one sequence, hsa-miR-6727-5p, in the process of wound healing in vitro
An equivalent staining pattern was observed for human adult dermal fibroblasts (HDFa); increased conversion of MTT to formazan was observed at 20 μg mL−1 HDL (32.3 ± 7.14%; p < 0.05) compared to the control (Figure 1C)
Summary
Non-healing wounds are a significant cause of morbidity and mortality in the United Kingdom; according to The Health Improvement Network (THIN database), there were an estimated 3.8 million patients with a wound managed by the National Health Service (NHS) in 2017/2018, of which 89% and 49% of acute and chronic wounds healed, respectively, within the study year [1]. The process of wound healing involves four separate, but overlapping stages: haemostasis, inflammation, proliferation and remodelling [2–4]. Neutrophils enter the wound within less than an hour to eliminate bacteria, followed by macrophages within 48–72 h post-injury, which remove cell and matrix debris and contribute factors which mediate inflammatory responses, enhance angiogenesis and promote the formation of granulation tissue [3,4]. The ensuing formation of a vascular network of capillaries is associated with fibroblast proliferation, collagen deposition and migration of keratinocytes from wound edges, achieving re-epithelialisation [3,4]. Myofibroblasts aid wound contraction, limiting the area for re-epithelialisation, in a remodelling phase which involves degradation of surplus extracellular matrix, replacement of type III with type I collagen, cellular apoptosis and production of new cells [2–4]
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