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

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• 作者：Shathiyah Kulandavelu ; PhD^a ; Vasileios Karantalis ; MD^a ; Julia Fritsch ; BS^a ; Konstantinos E. Hatzistergos ; PhD^a ; Viky Y. Loescher ; MD^a ; Frederic McCall ; BS^a ; Bo Wang ; MD^a ; Luiza Bagno ; PhD^a ; Samuel Golpanian ; MD^a ; Ariel Wolf ; BS^a ; Justin Grenet ; BS^a ; Adam Williams ; MD^a ; Aaron Kupin^a ; Aaron Rosenfeld^a ; Sadia Mohsin ; PhD^b ; Mark A. Sussman ; PhD^b ; Azorides Morales ; MD^c ; Wayne Balkan ; PhD^a ; ^c ; Joshua M. Hare ; MD^a ; ^c ; ^{jhare@med.miami.edu}
• 关键词：heart failure ; human cardiac progenitor cells ; injection ; pressure volume
• 刊名：Journal of the American College of Cardiology
• 出版年：2016
• 出版时间：6 December 2016
• 年：2016
• 卷：68
• 期：22
• 页码：2454-2464
• 全文大小：3026 K
• 卷排序：68

文摘

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.ObjectivesThe authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI).MethodsHuman 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.ResultsWhereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a &sim;3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (&minus;29.2 &plusmn; 2.7% vs. &minus;8.4 &plusmn; 0.7%; p < 0.003). Pim1+ hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 &plusmn; 7.2% vs. 65.6 &plusmn; 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).ConclusionsPim1 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.