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.
Department of Ophthalmology, Indiana University, Indianapolis, IN.
Ashay D
AD
Bhatwadekar
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL.
Yuanqing
Y
Yan
BetaStem Therapeutics, Sausalito, CA.
Valerie
V
Stepps
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL.
Sugata
S
Hazra
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL.
Maria
M
Korah
BetaStem Therapeutics, Sausalito, CA.
Stephen
S
Bartelmez
Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY.
Brahim
B
Chaqour
Department of Ophthalmology, Indiana University, Indianapolis, IN mabgrant@iupui.edu.
Maria B
MB
Grant
D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000097:blood / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D056926:CLOCK Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003930:Diabetic Retinopathy / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D066026:Endothelial Progenitor Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D010455:Peptides / Q000378:metabolism; D056950:Period Circadian Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D015415:Biomarkers; D056926:CLOCK Proteins; D015820:Cadherins; D006023:Glycoproteins; D035683:MicroRNAs; D010455:Peptides; D056950:Period Circadian Proteins; D051193:Toll-Like Receptors; D000099152:Cadherin 5; C541874:MIRN92 microRNA, human; C421902:PER2 protein, human