Long noncoding RNA H19 acts as a miR‐29b sponge to promote wound healing in diabetic foot ulcer

Abstract

Aberrant expression of long noncoding RNA (lncRNA) H19 and microRNA (miR)-29b has been implicated in the complications of diabetes mellitus (DM). As a common and important complication of DM, diabetic foot ulcer (DFU) is characterized by high incidence and poor prognosis. Herein, we explored the role of lncRNA H19 in wound healing of DFU. Differentially expressed DM-related lncRNAs were initially screened by microarray data analysis. DFU models were then induced in DM mouse models. The functional role and interaction of lncRNA H19, miR-29b and FBN1 in DFU were subsequently determined by examining the proliferation, migration, and apoptosis of fibroblasts after silencing H19, inhibiting or overexpressing miR-29b and FBN1. According to microarray-based analysis, lncRNA H19 was upregulated in DM. In the ulcerative edge tissues of DFU, high expression of lncRNA H19 and FBN1 and low expression of miR-29b were observed. FBN1 was identified to be a target gene of miR-29b. LncRNA H19 could competitively bind to miR-29b, and then, inhibited its expression, which consequently upregulating FBN1. Silencing of lncRNA H19 led to inhibited proliferation, migration, and enhanced apoptosis of fibroblasts, accompanied by downregulated FBN1 but upregulated miR-29b, which diminished the expression of TGF-β1, Smad3, FN, and Col-1 and reduced extracellular matrix accumulation. Altogether, upregulation of lncRNA H19 can elevate the expression of FBN1 through competitively binding to miR-29b, which enhances the proliferation, migration, and inhibits apoptosis of fibroblasts, thus facilitating the wound healing of DFU.

Epigenetic regulation of cellular functions in wound healing

“…Moreover, ectopic overexpression of lncRNA H19 in DFU fibroblasts reduced miR-29b level, resulting in upregulation of FBN1 (Fibrillin 1). 31 These data support therapeutic application of MSC-derived exosomes carrying lncRNA H19 for improved diabetic fibroblast function. 30 A study by Hu et al 32 showed that lncRNA URIDS (Upregulated in Diabetic Skin) is highly expressed in diabetic skin and upregulated in dermal fibroblasts treated with advanced glycation end products (AGE).…”

Emerging Roles of Long Non-Coding RNAs in Diabetic Foot Ulcers

“…Li et al detected that the expression of H19 and Fibrillin 1 (FBN1) was higher and the expression of miR-29b was lower in the wound tissues of DFU patients. 103 FBN1 is a major component of microfibrils in the ECM and is one of the target genes of miR-29b. 104 They demonstrated that the proliferation and migration of fibroblasts extracted from DFU patients were promoted, while the apoptosis of the cell line was suppressed, when H19 and FBN1 were overexpressed and miR-29b was silenced.…”

Modulation of Mesenchymal Stem Cells for Enhanced Therapeutic Utility in Ischemic Vascular Diseases

“…CM is a rich source of extracellular vesicles that encompass a variety of molecular agents, nucleic acids, and proteins. In vitro, R28 retinal cells under stress from oxygen-glucose deprivation (OGD) exposed to MSC-derived EVs significantly minimized the rate of apoptosis and rescued cells from OGD stress [ 91 ]. In support of this, endocytosis of EVs, when delivered into the vitreous cavity, significantly reduced the levels of caspase-3 proteins in the retinal ischemia model [ 91 ].…”

“…In vitro, R28 retinal cells under stress from oxygen-glucose deprivation (OGD) exposed to MSC-derived EVs significantly minimized the rate of apoptosis and rescued cells from OGD stress [ 91 ]. In support of this, endocytosis of EVs, when delivered into the vitreous cavity, significantly reduced the levels of caspase-3 proteins in the retinal ischemia model [ 91 ]. Since a variety of miRNAs are found in EVs isolated from MSCs, few studies have explored the association of miRNA in exosomes in retinal ischemia.…”