Abstract 13386: Persistence of Transplanted Explant-derived Human Cardiac Stem Cells Contributes to Therapeutic Regeneration of Injured Mycardium
Introduction: Cardiac stem cells (CSCs) mediated improvements in cardiac function have been attributed to the rescue of reversibly damaged tissue, proliferation of endogenous cells and differentiation of transplanted CSCs into new myocardium. Despite evidence that CSC therapy improves post-ischemic function, controversy surrounds the extent to which physical incorporation and persistence of transplanted cells contributes to the benefits of CSC therapy. In this study, we use “on demand” ablation of transplanted CSCs to dissect the contribution of engrafted cells to myocardial repair.
Methods/Results: Diphtheria toxin (DT) was used to induce transplanted human cell death. Human CSCs were cultured from atrial appendage biopsies obtained during clinically-indicated surgery. Exposure of human CSCs to DT prompted expression of annexin V ± propidium iodide in 37±10% of treated cells within 12 hours (p≤0.05 vs. human CSCs not exposed to DT) and resulted in a progressive decline in viable human cell counts (Figure A); suggesting that DT may provide the ideal means of ablating transplanted human sourced cells within a DT resistant host. The influence of short term persistence of transplanted CSCs was investigated in a series of SCID mice by applying DT or vehicle 1 week after intra-myocardial injection of human CSCs (Figure B). A decline in the ejection fraction in CSC-treated mice underscores the importance of transplanted cell persistence on CSC-mediated cardiac repair. This decrease was paralleled by increases in scar size (1.4±1.0 fold greater % scar, p=0.05), reduced contractility (1.2±0.1 fold lower dP/dT max, p=0.04) and impaired relaxation (1.6±0.2 fold lower dP/dT min, p=0.05) as compared to mice that received CSCs alone.
Conclusions: Elimination of CSCs 1 week after transplantation reduces CSC-mediated cardiac repair- suggesting that persistent paracrine secretion and/or cell replacement contribute to the maintenance of therapeutic regeneration.
Author Disclosures: E. Richardson: None. S. Mount: None. A.E. Mayfield: None. G. Rafatian: None. N. Latham: None. D.J. Stewart: None. D.R. Davis: None.
- © 2015 by American Heart Association, Inc.