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

Diabetes. 2015 Dec;64(12):4226-37. doi: 10.2337/db15-0521. Epub 2015 Aug 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Antigens, CD / metabolism
  • Antigens, CD34 / blood
  • Antigens, CD34 / metabolism
  • Biomarkers / blood
  • Biomarkers / metabolism
  • CLOCK Proteins / antagonists & inhibitors
  • CLOCK Proteins / blood
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Cadherins / metabolism
  • Cell Differentiation*
  • Cells, Cultured
  • Cohort Studies
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / immunology
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology
  • Diabetic Retinopathy / blood
  • Diabetic Retinopathy / immunology
  • Diabetic Retinopathy / metabolism
  • Diabetic Retinopathy / pathology*
  • Down-Regulation
  • Endothelial Progenitor Cells / immunology
  • Endothelial Progenitor Cells / metabolism
  • Endothelial Progenitor Cells / pathology*
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology*
  • Gene Expression Profiling
  • Glycoproteins / metabolism
  • Humans
  • MicroRNAs / metabolism*
  • Middle Aged
  • Peptides / metabolism
  • Period Circadian Proteins / antagonists & inhibitors
  • Period Circadian Proteins / blood
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism*
  • RNA Interference
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism

Substances

  • AC133 Antigen
  • Antigens, CD
  • Antigens, CD34
  • Biomarkers
  • Cadherins
  • Glycoproteins
  • MIRN92 microRNA, human
  • MicroRNAs
  • PER2 protein, human
  • Peptides
  • Period Circadian Proteins
  • Toll-Like Receptors
  • cadherin 5
  • CLOCK Proteins