Background: Pim-1 kinase plays an important role in cell division, survival and commitment towards myocardial lineage. We hypothesized that Pim-1 overexpression in ckit+ cardiac stem cell (CSCs) enhances cardioreparative effects.
Methods: Immunosuppressed Yorkshire swine (n=31) received human ckit+ CSCs (n=9), Pim1 modified human ckit+ CSCs (n=9) or PBS (n=13) two weeks after myocardial infarction. Cardiac MRI and PV loops were obtained before and after cell administration.
Results: At 8 weeks post transplantation, scar mass (Fig. 1A), viable tissue (Fig. 1B), ejection fraction (Fig. 1C) and stroke work (Fig. 1D) was significantly improved in Pim-1 modified ckit+ CSC compared to control ckit+, while both cell groups showed partial recovery compared to placebo (two way ANOVA, p<0.05). Both cell types similarly reduced preload (end diastolic pressure; Fig. 1E) and afterload (Arterial elastance; Fig 1F) compared to placebo, while only administration of Pim-1 CPCs improved regional contractility at both the infarct (Fig. 1G) and border zones (Fig. 1H). Collectively, mechanoenergetic recoupling was superior in the Pim-1 group compared to ckit+ controls (Cardiac Efficiency; Fig. 1I).
Conclusions: Cardioreparative potential of CSCs delivered by intramyocardial injection to infarcted porcine hearts is significantly enhanced by overexpress Pim1, supporting translational development of Pim-1 as a validated genetic modification of CSCs for incorporation into clinical trials.