De-differentiation of adult somatic cells into multipotent progenitor cells might provide an attractive and alternative source for therapeutic cloning to generate pluripotent, autologous stem cells for regenerative medicine. Currently, the benefit of adult stem cell therapies appears to be limited to vascular repair without affecting myogenesis and/or myocardial regeneration. While improved vascularization appears to have the real potential clinical benefit of endothelial progenitor cells (EPC) therapy in patients with acute myocardial infarction and chronic heart failure, achieving the consistent regeneration of cardiac myocytes would still of great interest. We tested the hypothesis that the treatment of EPC with chromatin modifying agents Trichostatin A (inhibitor for histone deacetylase) and 5Aza-2-deoxycytidine (inhibitor for DNA methylation) influence histone acetylation and DNA methylation respectively thereby modify the chromatin structure and up-regulates embryonic stem gene expression. We report that 1) 5Aza and TSA treatment of EPC induces pluripotent genes Oct4, and Nanog and down regulates endothelial cell lineage specific genes. 2) Under specific culture conditions, treated EPCs showed effective trans-differentiation into ectoderm (neuronal), and mesoderm (cardiomyocyte) lineages. 3) The treated EPC showed increased AceH3K9 and decreased HDAC1 and LSD1 activity than the control cells. Taken together this biochemical and molecular data provide a novel and oocyte-independent approach for the generation of functional autologous stem like cells from adult progenitor cells without the introduction of retroviral mediated trans-genes or ES cell fusion for future use in regenerative medicine.

Public Health Relevance

Currently, the benefit of adult stem-cell therapy appears to be limited to vascular repair;myogenesis and/or myocardial regeneration seem to be unaffected. Although the potential for improved vascularization with EPC therapy will likely provide considerable clinical benefit to patients with acute myocardial infarction and chronic heart failure, techniques that can consistently regenerate cardiac myocytes are still of great interest. Thus, the development of autologous stem cells with enhanced lineage plasticity for subsequent testing in the setting of myocardial ischemia is an integral part of stem-cell research and it could be effectively used in cell therapy for regenerative medicine.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Buxton, Denis B
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University of Kansas
Internal Medicine/Medicine
Schools of Medicine
Kansas City
United States
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