TUG1 enhances high glucose-impaired endothelial progenitor cell function via miR-29c-3p/PDGF-BB/Wnt signaling

Yang Li,Shilong Han,Maoquan Li,Weishuai Lian,Haijun Zhang,Xiaoping Zhang,Xue Li,Kangkang Zhi

doi:10.1186/s13287-020-01958-3

Abstract

BackgroundDiabetes is associated with the dysfunction of endothelial progenitor cells (EPCs), characterized as impaired angiogenesis, a phenomenon thought to be involved in the development of diabetic foot. lncRNA plays an essential role in microvascular dysfunction and signaling pathways in patients with diabetes. lncRNA taurine upregulated gene 1 (TUG1) participates in angiogenesis in various cells. However, the mechanisms of TUG1 activity in EPCs have not been elucidated.MethodsWe isolated and then characterized EPCs from the peripheral blood of mice using immunofluorescence and flow cytometry. Western blot detected the wnt/β-catenin pathway in high glucose-treated EPCs. Bioinformatics analysis predicted a putative binding site for TUG1 on miR-29c-3p. The interactions among TUG1, platelet-derived growth factor-BB (PDGF-BB), and miR-29c-3p were analyzed by luciferase assays. In vivo, diabetic mouse ischemic limb was treated with normal saline or TUG1 overexpression lentiviruses.ResultsWe found that EPC migration, invasion, and tube formation declined after treatment with high glucose, but improved with TUG1 overexpression. Mechanically, wnt/β-catenin pathway and autophagy were involved in the function of TUG1 overexpression in high glucose-treated EPCs. Moreover, TUG1 regulates the PDGF-BB/wnt pathway and function of high glucose-treated EPCs via miR-29c-3p. In vivo, injection of TUG1 lentivirus in a diabetic mouse ischemic limb model stimulated angiogenesis.ConclusionsOur findings suggest that TUG1 restores high glucose-treated EPC function by regulating miR-29c-3p/PDGF-BB/Wnt signaling.

Highlights

Diabetic foot syndrome (DFS) is one of the most common complications of diabetes mellitus, both type 1 and type 2, and it is the leading cause of hospitalization in patients with type 2 diabetes [1]
We confirmed that the cultured cells expressed endothelial-specific markers such as CD34, CD133, and VEGFR-2, all of which are characteristic of endothelial progenitor cells (EPCs) (Fig. 1b)
Overexpression of taurine upregulated gene 1 (TUG1) restored the function of EPCs treated with high glucose As previously indicated TUG1 plays a vital role in angiogenesis, decreased expression of TUG1 was found in EPCs under high glucose (Supplementary Fig. S1)

Summary

Introduction

Diabetic foot syndrome (DFS) is one of the most common complications of diabetes mellitus, both type 1 and type 2, and it is the leading cause of hospitalization in patients with type 2 diabetes [1]. Several new compelling lines of evidence suggest that the final common etiology may involve stem cell dysfunction, endothelial progenitor cells (EPCs) [4]. Hypoxia is pathologically associated with diabetes, but a study indicated that EPCs are significantly decreased (40%) in diabetic patients with peripheral vascular disease [9]. Many studies on animal models and humans agree that EPCs and CPCs are highly affected in diabetes, and proper migration, differentiation, and proliferation of EPCs are vital for vascular neogenesis in DFS [10,11,12]. Diabetes is associated with the dysfunction of endothelial progenitor cells (EPCs), characterized as impaired angiogenesis, a phenomenon thought to be involved in the development of diabetic foot. The mechanisms of TUG1 activity in EPCs have not been elucidated

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Results

Conclusion