Abstract 17146: Human Cardiosphere-Derived Cells From Advanced Heart Failure Patients Exhibit Augmented Functional Potency in a Mouse Model of Myocardial Infarction
Background: Preclinical studies and an on-going clinical study (CADUCEUS) support the notion that cardiosphere-derived cells (CDCs) from normal and recently-infarcted hearts are capable of reducing scar size and boosting cardiac function. It is unknown whether CDCs from advanced heart failure patients retain the same functional benefit.
Methods and Results: In a mouse model of acute MI, we compared the regenerative potential of CDCs derived from 3 groups (N=6 patients in each group): 1) Normal: healthy donor hearts post-transplantation; 2) Recent MI: patients who had an MI 17-27 days before biopsy; 3) HF: hearts with dilated cardiomyopathy explanted at cardiac transplantation. A control (PBS) injection group was included. MI was induced in SCID mice by LAD ligation and 105 CDCs were injected intramyocardially in the MI border zone. Echocardiographic images were analyzed independently in a blinded manner. The LVEFs two hours post-MI were comparable, indicating similar initial injury among groups. Over the 3 week time course, LVEF deteriorated in the Control group while all CDC-treated groups exhibited preservation of cardiac function. 3 weeks after treatment, the highest LVEF was seen in the mice that had received HF CDCs (HF: 37.1±10.1%; Recent MI: 27.6±9.8%; Normal: 27.0±9.2%; N=6 [patients]; n=19-24[mice]; p<0.05 via One-way ANOVA with LSD post test). Flow cytometry revealed a somewhat larger fraction of c-kit+ cells in the HF CDCs (HF: 6.3±2.7%; Recent MI: 3.6±1.4%; Normal: 3.9±3.4%). Secretion of VEGF, HGF, IGF, and SDF-1 from cultured CDCs was measured by ELISA. Gene expressions of GATA-4, MEF2C, ZFRM1, FDR, HDAC2, ITA2a and LAMB1 were assessed by RT-PCR. Tube formation assay was performed as an indicator of angiogenesis. None of these in vitro CDC parameters differed significantly among groups nor did any strongly correlate with cardiac function in vivo. Interestingly, we detected a moderate positive correlation between patient age and cardiac function (R=0.4, p=0.07).
Conclusions: Our data contradict the routine assumption that stem cells from younger donors without heart failure are superior for therapeutics. Indeed, CDCs from advanced heart failure patients exhibit augmented functional potency in a mouse model of myocardial infarction.
- © 2011 by American Heart Association, Inc.