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Published on: February 17, 2023
Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer
Sushant Bhattacharya1, Rangoli Aggarwal1, Vijay Pal Singh1
1Council of Scientific and Industrial Research (CSIR), Institute of Genomics and Integrative Biology, Delhi, India.
Abstract:
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 microRNAs (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 downregulated in diabetic rat wounds (as compared with normal rat wound, d 7 postwounding) 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 downregulation. Compared with unwounded skin, Dicer levels were significantly upregulated 12 d postwounding in normal rats, and this result was notably absent in diabetic rats that showed impaired wound closure. In a wound-healing specific quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) array, 10 genes were significantly altered in the diabetic rat wound and included growth factors and collagens. Network analyses demonstrated significant interactions and correlations between the miRNA predicted targets (regulators) and the 10 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.
Insights
Diabetic wound healing is impaired due to altered microRNA (miRNA) signatures and reduced Dicer enzyme levels, impacting inflammatory responses and gene regulation crucial for skin repair.
Area of Science:
- Biomedical Science
- Molecular Biology
- Dermatology
Background:
- Diabetes mellitus is a significant risk factor for delayed wound healing.
- The molecular mechanisms underlying impaired wound closure in diabetes are complex and not fully understood.
- MicroRNAs (miRNAs) play a role in cellular regulation, but their specific involvement in diabetic wound healing requires further investigation.
Purpose of the Study:
- To investigate the role of microRNAs (miRNAs) and Dicer in the delayed wound healing process associated with diabetes.
- To identify specific miRNA signatures and their target genes involved in impaired wound closure in diabetic rats.
- To explore the therapeutic potential of targeting Dicer and miRNAs for improving diabetic wound healing.
Main Methods:
- Comparative analysis of miRNA expression profiles in diabetic and normal rat wound tissues.
- Quantification of Dicer enzyme levels in unwounded skin and wound tissues at different time points post-wounding.
- Utilizing a wound-healing specific quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) array to identify altered genes.
- Performing network analyses to correlate miRNA targets with key wound-healing genes.
- In vitro experiments assessing the effect of Dicer inhibition on cell migration and wound closure in HaCaT cells.
Main Results:
- Diabetic rat wounds exhibited a distinct miRNA signature with significant downregulation of 19 miRNAs and decreased Dicer levels compared to normal wounds.
- Dicer levels were upregulated in normal wound healing but remained suppressed in diabetic wounds, correlating with impaired closure.
- Ten key wound-healing genes, including growth factors and collagens, were significantly altered in diabetic rat wounds.
- Network analysis revealed interactions between altered miRNAs and genes involved in wound closure.
- Inhibition of Dicer in HaCaT cells impaired cell migration and wound closure.
Conclusions:
- Altered miRNA profiles and reduced Dicer expression are critical factors contributing to delayed wound healing in diabetes.
- The identified miRNA signature and affected genes represent potential therapeutic targets for managing diabetic wound complications.
- Restoring Dicer and miRNA levels may offer a novel strategy to enhance wound closure in diabetic patients.
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