Changes in miroRNA‐103 expression in wound margin tissue are related to wound healing of diabetes foot ulcers

Abstract

To investigate the relationship between small noncoding microRNA-103 (miR-103) and wound healing of diabetic foot ulcers (DFU) and the underlying molecular mechanism, forty type 2 diabetes mellitus with DFU (DFU group), and 20 patients with a chronic skin ulcer of lower limbs and normal glucose tolerance (SUC group) were included. Quantitative real-time PCR method was used to determine miR-103 expression levels in the wound margin tissue of subjects, and to analyse the relationship between the expression of miR-103 and DFU wound healing. In vitro experiments were also performed to understand the effect of miR-103 on the high glucose-induced injury of normal human dermal fibroblasts (NHDFs) cells. The results showed that the miR-103 expression level in the DFU group was significantly higher than that in the SUC group [5.81 (2.25-9.36) vs 2.08 (1.15-5.72)] (P < 0.05). The expression level of miR-103 in the wound margin tissue of DFU was negatively correlated with the healing rate of foot ulcers after four weeks (P = 0.037). In vitro experiments revealed that miR-103 could inhibit the proliferation and migration of NHDF cells and promote the apoptosis of NHDF cells by targeted regulation of regulator of calcineurin 1 (RCAN1) gene expression in a high glucose environment. Downregulation of miR-103 could alleviate high glucose-induced NHDF cell injury by promoting RCAN1 expression. Therefore, the increased expression of miR-103 is involved in the functional damage of NHDF cells induced by high-glucose conditions, which is related to poor wound healing of DFU.These research findings will provide potential targets for the diagnosis and treatment of chronic skin wounds in diabetes. K E Y W O R D S foot ulcer, human dermal fibroblasts, miR-103, RCAN1, type 2 diabetets Xiaotong Zhao and Murong Xu contributed equally to this study.

MicroRNAs involved in human skin burns, wound healing and scarring

“…Samples used to study burn-related miRNAs include adult skin fibroblasts, [18][19][20][21] skin epidermal stem cells, 22 skin, [23][24][25][26][27] wound tissues 28,29 and hypertrophic scar (HS) tissues. [30][31][32][33] Samples used to study wound-healing related miRNAs include healthy skin, [34][35][36] chronic non-healing ulcer tissue, 37,38 epidermal keratinocytes 39 and the HaCaT cell line. [40][41][42][43][44] HS tissues were used to study scarring-related miRNAs.…”

“…Other techniques include microarrays (miRCURY LNA, Affymetrix GeneChip, and Agilent) and high throughput sequencing. Although qRT-PCR is the most commonly used technique, only 58 miRNAs were identified in the 27 articles that utilised the technique, [18][19][20][21][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][45][46][47][48][49][50] while the expression level of 82 miRNAs were measured by sequencing in two research studies. 22,38 In comparison, alterations in the expression of 203 miRNAs were detected using three different microarrays in seven research studies.…”

“…A total of 89 miRNAs have been associated with wound healing, identified from 11 research papers [34][35][36][37][38][39][40][41][42][43][44] (Table 1 and Table 2). Only hsa-miR-31 and hsa-miR-132 have been studied in two papers while the other miRNAs were investigated in only one research study each.…”

Effect and mechanism of microRNAs on various diabetic wound local cells

“…28 Downregulation of miR-103 mitigated hyperglycemia-induced HSF injury by promoting RCAN1 expression, so it can promote wound repair by inhibiting the expression of miR-103. 28 Another study found that miR-27-3p was overexpressed in the wounds of diabetic mice and patients. The decreased level of its downstream target neurooncological ventral antigen 1 in fibroblasts was shown to cause less proliferation and extracellular matrix production but more apoptosis.…”

Puffball spores improve wound healing in a diabetic rat model

“…A study found that patients with DFUs had a much 2.5-fold higher risk of death than patients without lower extremity wounds, with an estimated 5-year mortality rate of 42% for patients with DFUs ( 4 ). Although various drugs are availabled for DFUs, the ulcers usually remain refractory and impact the quality of life of patients ( 5 ). Therefore, it is essential to investigate new strategies to accelerate healing of these cutaneous ulcers.…”