Open AccessAbnormal DNA Methylation Induced by Hyperglycemia Reduces CXCR 4 Gene Expression in CD 34 + Stem Cells
Author(s) -
Vigorelli Vera,
Resta Jessica,
Bianchessi Valentina,
Lauri Andrea,
Bassetti Beatrice,
Agrifoglio Marco,
Pesce Maurizio,
Polvani Gianluca,
Bonalumi Giorgia,
Cavallotti Laura,
Alamanni Francesco,
Genovese Stefano,
Pompilio Giulio,
Vinci Maria Cristina
Publication year - 2019
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.118.010012
Subject(s) - stem cell , dna methylation , epigenetics , microbiology and biotechnology , progenitor cell , cancer research , medicine , biology , endocrinology , gene expression , gene , biochemistry
Background CD 34 + stem/progenitor cells are involved in vascular homeostasis and in neovascularization of ischemic tissues. The number of circulating CD 34 + stem cells is a predictive biomarker of adverse cardiovascular outcomes in diabetic patients. Here, we provide evidence that hyperglycemia can be “memorized” by the stem cells through epigenetic changes that contribute to onset and maintenance of their dysfunction in diabetes mellitus. Methods and Results Cord‐blood–derived CD 34 + stem cells exposed to high glucose displayed increased reactive oxygen species production, overexpression of p66 shc gene, and downregulation of antioxidant genes catalase and manganese superoxide dismutase when compared with normoglycemic cells. This altered oxidative state was associated with impaired migration ability toward stromal‐cell–derived factor 1 alpha and reduced protein and mRNA expression of the C‐X‐C chemokine receptor type 4 ( CXCR 4) receptor. The methylation analysis by bisulfite Sanger sequencing of the CXCR 4 promoter revealed a significant increase in DNA methylation density in high‐glucose CD 34 + stem cells that negatively correlated with mRNA expression (Pearson r =−0.76; P =0.004). Consistently, we found, by chromatin immunoprecipitation assay, a more transcriptionally inactive chromatin conformation and reduced RNA polymerase II engagement on the CXCR 4 promoter. Notably, alteration of CXCR 4 DNA methylation, as well as transcriptional and functional defects, persisted in high‐glucose CD 34 + stem cells despite recovery in normoglycemic conditions. Importantly, such an epigenetic modification was thoroughly confirmed in bone marrow CD 34 + stem cells isolated from sternal biopsies of diabetic patients undergoing coronary bypass surgery. Conclusions CD 34 + stem cells “memorize” the hyperglycemic environment in the form of epigenetic modifications that collude to alter CXCR 4 receptor expression and migration.