Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine

Abstract Background Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit + cardiac stem cells (CSCs) enhances their cardioreparative properties. Objectives The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI). Methods Human cardiac stem cells (hCSCs, n = 10), hckit + CSCs overexpressing Pim1 (Pim1 + ; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration. Results Whereas both hCSCs reduced MI size compared to placebo, Pim1 + cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (−29.2 ± 2.7% vs. −8.4 ± 0.7%; p  + hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p  + group at 8 weeks compared to placebo. Both hCSC and Pim1 + hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1 + hCSC group (p = 0.005). Conclusions Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.