biostudies-literatureKulandavelu SNHLBI NIH HHS2454-2464https://www.ebi.ac.uk/biostudies/studies/S-EPMC5223744biostudies-literatureUnknown68(22)<h4>Background</h4>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.<h4>Objectives</h4>The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI).<h4>Methods</h4>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.<h4>Results</h4>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 < 0.003). Pim1⁺ 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 <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1⁺ 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).<h4>Conclusions</h4>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.Journal of the American College of CardiologyPim1 Kinase Overexpression Enhances ckit⁺ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine.PMC5223744R01 HL122525R01 HL117163R01 HL110737R37 HL091102R01 HL137355R01 HL107110R01 HL105759R01 HL113647R01 HL084275P01 HL085577R01 HL067245UM1 HL113460Hatzistergos KEBalkan WKarantalis VWang BLoescher VYMohsin SWilliams AHare JMKulandavelu SSussman MAMorales AFritsch JBagno LWolf AKupin AMcCall FGrenet JRosenfeld AGolpanian SfalsePim1 Kinase Overexpression Enhances ckit⁺ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine.<h4>Background</h4>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.<h4>Objectives</h4>The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI).<h4>Methods</h4>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.<h4>Results</h4>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 < 0.003). Pim1⁺ 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 <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1⁺ 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).<h4>Conclusions</h4>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.2016-01-01T00:00:00Z2016 Dec2026-05-05T14:59:01.222Z2019-03-27T02:33:46ZS-EPMC52237442790835110.1016/j.jacc.2016.09.925