Abstract 13259: Irrelevance of C-Kit-Positive Subpopulation to the Therapeutic Benefit of Human Cardiosphere-Derived Cells
Background: The regenerative potential of cardiosphere-derived cells (CDCs) has been demonstrated in various animal models and in the recently-completed CADUCEUS clinical trial. CDCs contain a small (typically 3-10%) fraction of ckitPOS cells, which have been posited to be cardiac progenitors. We tested the hypothesis that the ckitPOS subpopulation is critical for the regenerative benefit of CDCs, using data from a mouse model and the CADUCEUS trial.
Methods and Results: MI was induced in SCID mice (n=6-8 mice) by LAD ligation and 105 natural CDCs or ckitNEG CDCs (CDCs depleted of ckitPOS cells by MACS) were injected intramyocardially in the MI border zone. Masson’s trichrome staining of heart sections (A) and heart morphometry 3 weeks after MI revealed adverse LV remodeling in Control (vehicle injection), while treatment with CDCs or ckitNEG CDCs led to similar improvements in heart morphology (with thicker infarct walls [B] and more viable tissue in the infarct [C] compared to Control). LVEFs two hours post-MI were comparable, indicating similar initial injury among groups (D). Over the 3 week post-MI time course, LVEF deteriorated in Control while CDC- or ckitNEG CDC-treated animals had improved cardiac function (E), which was indistinguishable between the two cell therapy groups. We further found that the percentage of ckitPOS cells in CDC-treated CADUCEUS patients was unrelated to regenerative efficacy: Linear regression analysis revealed no correlation between ckitPOS% (range: 0.3-7.2%; mean±s.d.: 3.2±2.0%, n=10) and changes in viable mass [F] or scar size [G].
Conclusions: In a mouse model of MI, natural CDCs and ckit-depleted CDCs have the same therapeutic benefit. In a clinical trial, the ckitPOS% is not correlated to the clinical outcomes of CDC treatment. Thus, the ckitPOS subpopulation is irrelevant to the functional or regenerative efficacy of CDCs.
- © 2012 by American Heart Association, Inc.