Abstract 19310: Cellular Metabolism Regulates Stemness of Cardiac Progenitor Cells
Introduction: Autologous stem cell therapy holds potential for myocardial repair and rejuvenation, yet has shown mixed results and would benefit from greater understanding of the role played by c-kit+ cardiac progenitor cells (CPC). CPCs have been used in clinical trials to treat heart failure after acute myocardial infarction, but experimental studies have yielded mixed results for efficacy and mechanism. One potential explanation for discrepant findings may be heterogeneity in progenitor “stemness”, with only a small minority of the cell population possessing key features of true cardiac stem cells. Strategies aimed at promoting a more primitive cell state may improve CPC-based therapy. In hematopoietic and neural stem cells, preservation of “stemness” is dependent on low oxidative metabolism within a hypoxic niche.
Hypothesis: Stem cell qualities of CPCs from adult human patients are augmented by increasing glycolytic metabolism and inhibiting mitochondrial respiration.
Methods and Results: Glycolysis was increased in CPCs treated with the mitochondrial ATP synthase inhibitor oligomycin. Proliferation rates were not significantly different in CPCs cultured in 1 ng/ml and 10 ng/ml oligomycin for up to 14 days, compared with untreated cells, although oligomycin-treated cells underwent an initial lag phase in proliferation. Importantly, stem cell markers including NANOG and OCT4 were increased in CPCs after 1 week of oligomycin treatment. In comparison, proliferation was substantially increased in CPCs that had been isolated and maintained in hypoxia (1% O2) versus CPCs isolated and expanded in atmospheric oxygen (20% O2). Expression of stem cell marker genes KLF4 and OCT4 were also higher in CPCs in hypoxia versus atmospheric O2. Thus, isolation and expansion of CPCs in hypoxia likely preserves a higher level of stemness versus expansion in relative hyperoxia.
Conclusions: CPC stem-like qualities are maintained by limiting mitochondrial respiration through chemical inhibition or by hypoxia. Modification of culture conditions to modulate metabolism may be a viable approach to improving therapeutic efficacy through enhancing CPC stem-like qualities.
Author Disclosures: D.A. Kubli: None. K.I. Korski: None. M.A. Sussman: None.
- © 2016 by American Heart Association, Inc.