miR-92a Corrects CD34+ Cell Dysfunction in Diabetes by Modulating Core Circadian Genes Involved in Progenitor Differentiation

• DOI: 10.2337/db15-0521
• Publication Date: 2015-08-18T01:59:53Z
• Authors: Ashay D. Bhatwadekar; Yuanqing Yan; Valerie Stepps; Sugata Hazra; Maria Korah; Stephen Bartelmez; Brahim Chaqour; Maria B. Grant
• Keywords: 0301 basic medicine; Complications; Diabetic Retinopathy; Gene Expression Profiling; CLOCK Proteins; Down-Regulation; Antigens, CD34; Cell Differentiation; Middle Aged; Cadherins; Cohort Studies; MicroRNAs; 03 medical and health sciences; Antigens, CD; Diabetes Mellitus; Humans; AC133 Antigen; Endothelium, Vascular; Peptides; Biomarkers; Cells, Cultured; Endothelial Progenitor Cells; Glycoproteins

Autologous CD34+ cells are widely used for vascular repair; however, in individuals with diabetes and microvascular disease these cells are dysfunctional. In this study, we examine expression of the clock genes Clock, Bmal, Per1, Per2, Cry1, and Cry2 in CD34+ cells of diabetic and nondiabetic origin and determine the small encoding RNA (miRNA) profile of these cells. The degree of diabetic retinopathy (DR) was assessed. As CD34+ cells acquired mature endothelial markers, they exhibit robust oscillations of clock genes. siRNA treatment of CD34+ cells revealed Per2 as the only clock gene necessary to maintain the undifferentiated state of CD34+ cells. Twenty-five miRNAs targeting clock genes were identified. Three of the miRNAs (miR-18b, miR-16, and miR-34c) were found only in diabetic progenitors. The expression of the Per2-regulatory miRNA, miR-92a, was markedly reduced in CD34+ cells from individuals with DR compared with control subjects and patients with diabetes with no DR. Restoration of miR-92a levels in CD34+ cells from patients with diabetes with DR reduced the inflammatory phenotype of these cells and the diabetes-induced propensity toward myeloid differentiation. Our studies suggest that restoring levels of miR-92a could enhance the usefulness of CD34+ cells in autologous cell therapy.