MiR-92a corrects CD34⁺ cell dysfunction in diabetes by modulating core circadian genes involved in progenitor differentiation

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.