The development of novel treatments for lymphedema is hindered by the poorly understood pathophysiology of the disease. To improve the therapeutic success of treating the disease, the present study aimed to investigate the effects and mechanism of long non‑coding RNA myocardial infarction‑associated transcript (MIAT) in terms of the differentiation of adipose‑derived mesenchymal stem cells (ADMSCs) into lymphatic endothelial cells (LECs). The expression levels of (MIAT), microRNA (miR)‑495 and Prospero‑related homeobox 1 (Prox1) were measured by reverse transcription‑quantitative PCR. The protein expression levels of Prox1, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE‑1), vascular endothelial growth factor receptor‑3 (VEGFR‑3) and podoplanin (PDPL) were detected by western blotting and immunofluorescence. A dual‑luciferase reporter assay was also used to detect the interaction between MIAT, miR‑495 and Prox1. In addition, migration and tube‑formation capabilities were measured by Transwell assay and tube‑formation assay, respectively. The results obtained demonstrated that VEGF‑C156S (recombinant VEGF‑C in which Cys156 was replaced by Ser residue) treatment could efficiently induce the differentiation of ADMSCs into LECs. MIAT expression was upregulated and miR‑495 was downregulated during differentiation. Mechanistically, MIAT upregulated Prox1 expression possibly by acting as a molecular sponge for miR‑495. Functional analyses indicated that the expression levels of Prox1, LYVE‑1, VEGFR‑3 and PDPL, and the migration and tube‑formation capabilities of ADMSCs induced by VEGF‑C156S, were significantly inhibited by silencing MIAT and overexpressing miR‑495. Moreover, miR‑495 inhibition and Prox1 overexpression reversed the effects of MIAT downregulation and miR‑495 upregulation, respectively, on the differentiation of ADMSCs into LECs. Taken together, these results suggested that MIAT may be involved in the differentiation of ADMSCs into LECs, and that the MIAT/miR‑495/Prox1 axis may be a novel regulatory mechanism and therapeutic target for the treatment of lymphedema.
Keywords: lymphedema; long non‑coding RNA myocardial infarction associated transcript; adipose derived mesenchymal stem cells; microRNA‑495; Prospero‑related homeobox 1.