Allogeneic cardiosphere-derived cells (CDCs) have proven safe and effective in a small animal model of myocardial infarction (MI), and have been shown to act primarily via paracrine mechanisms to stimulate endogenous regeneration. The present translational study tested allogeneic CDCs in a large animal model (mini-pigs).
To establish a robust allogeneic model, all pigs were swine leukocyte antigen (SLA) typed by PCR. A male donor and female recipients with full SLA I, II mismatch were used. Pigs underwent balloon occlusion of the LAD for 2.5 hours, followed by reperfusion. Two weeks later, 12.5 million CDCs (n=8) or vehicle (n=6) were infused. Animals were sacrificed 2 weeks or 2 months post-infusion to assess the cellular (histology using a clinical rejection scale) and humoral (donor-specific antibodies, complement-dependent cytotoxicity) immune responses, as well as cardiac function (left ventriculography, hemodynamics, morphometry). Numerous in-life assessments for safety were performed and CDC engraftment was assessed by FISH for Y chromosome.
All immunological assays indicated an undetectable response to CDCs. Cardiac enzymes and systemic inflammation showed no differences between groups. There were no systemic histological findings related to CDCs. CDCs did not permanently engraft, with <0.1% persisting 2 weeks post-infusion and none evident 2 months post. Despite evanescent engraftment, functional benefits were seen following infusion of CDCs. Ejection fraction (EF) and infarct size (IS) were significantly improved in CDC-treated animals compared to vehicle-treated 2 weeks post-infusion (EF: 48.6±2.1% vs 38.2±2.6%, p<0.05; IS: 9±2 vs 14±2%, p<0.05). At 2 months, EF still trended higher in CDC-treated animals (42±5 vs 32±10%, p=0.09), and IS still trended lower (14±4 vs 16±7%, p=0.60). Pressure-volume relationships revealed a trend for enhanced contractility in CDC-treated animals (Emax: 3.2±2.2 vs 1.0±1.1 mmHg/mL, p=0.26). The magnitude of the functional benefits was similar to that seen in a prior pig study using autologous CDCs.
Overall, results of the present study demonstrate that allogeneic CDCs are largely equivalent to autologous in terms of efficacy, and elicit no detectable immunological response or safety concern.
P6416Introducing microvascular dysfunction in a large animal model of ST-elevation myocardial infarction