Abstract 16850: Diabetes Inhibits Cardiac Stem Cell-Mediated Cardiac Repair Through the Accumulation of Reactive Dicarbonyls
The impact of diabetes on cardiac stem cell (CSC) function is largely unknown yet critical given these are the very same individuals who may require CSC therapy in the future. As such, we tested the hypothesis that high glucose conditions impair CSC function.
Methods and Results: CSCs cultured from the cardiac biopsies of diabetic patients (HbA1c 10±2%) demonstrated reduced overall cell numbers as compared to non-diabetic sourced biopsies (0.5E6±0.2E6 vs. 1.2E6±0.2E6 cells; n=7, p=0.04). Conditioned medium (CM) from diabetic patient CSCs displayed a reduced ability to promote in vitro blood vessel formation (117±7 vs. 144±5 mm tube length with non-diabetic CSC-CM; n=3, p=0.02), while chemotactic activity in a migration assay was unaltered (n=3, p=0.2). When injected into the infarct border zone of immunodeficient mice one week after experimental myocardial infarction, CSCs sourced from diabetic patients demonstrated reduced cardiac repair as compared to non-diabetic CSCs (increase in ejection fraction 21 days after CSC transplantation 4±2 vs. 9±1%; n=3, p=0.03). CM from non-diabetic murine CSCs cultured in high (25mM) glucose conditions had a reduced capacity to promote in vitro blood vessel formation as compared to CM from CSCs cultured under physiological (5mM) glucose conditions (29±3 vs. 42±2 mm tube length, n=4, p=0.02). CM from CSCs cultured from the cardiac biopsies of streptozotocin-treated diabetic mice displayed a reduced capacity to promote in vitro blood vessel formation (37±3 vs. 59±5 mm tube length with non-diabetic CSC-CM; n=3, p=0.0008). The pro-angiogenic capacity of diabetic murine CSCs was restored when tissue was sourced from the cardiac biopsies of diabetic transgenic mice with constitutive over-expression of the methylglyoxal detoxification enzyme glyoxalase-1 (55±4 diabetic Tg vs. 53±2 non-diabetic Tg mm tube length; n=3, p=0.8).
Conclusions: Diabetes reduces the ability of CSCs to repair injured myocardium. Both diabetes and preconditioning CSCs in high glucose attenuated the pro-angiogenic capacity of CSCs. Increased expression of glyoxalase-1 restored the pro-angiogenic capacity of diabetic CSCs suggesting a means of reversing diabetic CSC dysfunction by interfering with the accumulation of reactive dicarbonyls.
- © 2013 by American Heart Association, Inc.