Transcriptional Network Analysis Reveals the Role of miR-223-5p During Diabetic Corneal Epithelial Regeneration

Abstract

Diabetes mellitus (DM) is a complex metabolic disorder. Long-term hyperglycemia may induce diabetic keratopathy (DK), which is mainly characterized by delayed corneal epithelial regeneration. MicroRNAs (miRNAs) have been reported to play regulatory roles during tissue regeneration. However, the molecular mechanism by which miRNAs influence epithelial regeneration in DK is largely unknown. In this study, we performed miRNA and mRNA sequencing of regenerative corneal epithelium tissue from streptozotocin-induced type 1 diabetic (T1DM) and wild-type mice to screen for differentially expressed miRNAs and mRNAs. Based on regulatory network analysis, miR-223-5p was selected for subsequent experiments and Hpgds was then identified as a direct target gene. MiR-223-5p downregulation significantly promoted diabetic corneal epithelial wound healing and nerve regeneration. However, the beneficial effects of miR-223-5p inhibition were abolished by an Hpgds inhibitor. Furthermore, mechanistic studies demonstrated that miR-223-5p suppression ameliorated inflammation and enhanced cell proliferation signaling in DK. Taken together, our findings revealed that the regulatory role of miR-223-5p in diabetic corneal epithelial and nerve regeneration by mediating inflammatory processes and cell proliferation signaling. And silencing miR-223-5p may contribute to the development of potential therapeutic strategies for DK.

Mechanistic investigations of diabetic ocular surface diseases

“…We also screened differentially expressed miRNAs in the regenerated corneal epithelium of normal and type 1 diabetic mice, and found that miR-223-5p was significantly upregulated, which may be involved in regulating the delay of diabetic corneal wound healing. In the next validation experiment, we confirmed that inhibition of miR-223-5p accelerated the regeneration of diabetic corneal epithelium and nerves, which mediates inflammation response and epithelial cell proliferation through its target gene Hpgds (203). In 2016, our group also found that miR-204-5p, which can directly regulate sirt1, has increased expression in diabetic corneas, and inhibition of miR-204-5p promotes corneal epithelial regeneration by accelerating cell cycle (204).…”

Tetrahedral DNA‐Based Functional MicroRNA‐21 Delivery System: Application to Corneal Epithelial Wound Healing

“…Since corneal wound healing is a complex process involving multiple sequential and parallel pathways, ribonucleic acids‐based therapies seem to be an attractive modality to multi‐targeted regulating several processes simultaneously for solving wound healing problems. Substantial studies have reported that several miRNAs were involved in the process of corneal healing, such as miR‐223, [ 22 ] miR‐21, [ 7 ] and miR‐31. [ 23 ] However, miRNA therapy still faces challenges.…”

Screening and analysis of differentially expressed circRNAs and miRNAs in chronic diabetic extremity wounds

“…For example, miR-223-5p, which has a network communication relationship with hsa_circRNA_104175, was significantly lower in megakaryocytes treated with high glucose. This suggests that miR-223-5p can negatively regulate platelet formation and affect platelet morphology and function in diabetic hyperglycemia, thereby accelerating atherosclerosis in peripheral tissues and promoting arterial thrombosis ( 34 ). The miR-223-5p of bone marrow derived can regulate the apoptosis and proliferation of vascular endothelial cells, that realize through NOD-like receptor signaling pathway of vascular endothelial cells and participate in the process of vascular injury in vascular related diseases ( 35 ).…”