Young-sup Yoon, MD, PhD [ View bio ](School of Medicine, Emory University)
Bone marrow-derived stem or progenitor cells such as mesenchymal stem cells (MSCs) or endothelial progenitor cells (EPCs) have been shown to be effective for repairing cardiovascular disease. However, recent studies have shown that autologous cells derived from diabetic patients are not as effective as those from non-diabetic or healthy volunteers. As many cardiovascular disease patients who are candidate for cell therapy have diabetes as co-morbid condition, new measures are required to reverse their dysfunction. By regulating chromatin structure, epigenetic changes play an essential role in controlling access to genes and regulatory elements in the genome. We found that MSCs or EPCs obtained from diabetic subjects have significant epigenetic changes in the promoter regions of key angiogenic factors and these defects reduce the functionality of the cells. Accordingly, we investigated whether reversing epigenetic alterations with small molecules can restore gene expression and cell biologic function of diabetic bone marrow-derived cells Genome-wide investigation of DNA methylation and histone modifications of diabetic cells identified the genes or loci that are most significantly affected by diabetes. By using various combinations of three classes of small molecules: DNA methyltransferase inhibitors, histone deacetylase (HDAC) inhibitors, and histone methyltransferase (HMT) inhibitors, we were able restore their angiogenic and tissue reparative genes in part. In addition, injection of these modified diabetic MSCs or EPCs in a hindlimb ischemia of diabetic animals enhanced angiogenic capacity and restored limb perfusion. Together small molecular epigenetic modifiers can reverse dysfunction of BM-derived stem and progenitor cells caused by diabetes and are effective for repairing tissue ischemia.
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