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Pim1 Kinase Overexpression Enhances ckit + Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine.
- Source :
-
Journal of the American College of Cardiology [J Am Coll Cardiol] 2016 Dec 06; Vol. 68 (22), pp. 2454-2464. - Publication Year :
- 2016
-
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 <superscript>+</superscript> cardiac stem cells (CSCs) enhances their cardioreparative properties.<br />Objectives: The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI).<br />Methods: Human cardiac stem cells (hCSCs, n = 10), hckit <superscript>+</superscript> CSCs overexpressing Pim1 (Pim1 <superscript>+</superscript> ; 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.<br />Results: Whereas both hCSCs reduced MI size compared to placebo, Pim1 <superscript>+</superscript> 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 <superscript>+</superscript> 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 <superscript>+</superscript> group at 8 weeks compared to placebo. Both hCSC and Pim1 <superscript>+</superscript> hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1 <superscript>+</superscript> hCSC group (p = 0.005).<br />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.<br /> (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Disease Models, Animal
Female
Fungal Proteins biosynthesis
Humans
Mitogen-Activated Protein Kinases biosynthesis
Myocardial Infarction enzymology
Myocardial Infarction genetics
Swine
Fungal Proteins genetics
Gene Expression Regulation
Mitogen-Activated Protein Kinases genetics
Myocardial Infarction surgery
Myocytes, Cardiac cytology
Stem Cell Transplantation methods
Subjects
Details
- Language :
- English
- ISSN :
- 1558-3597
- Volume :
- 68
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Journal of the American College of Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 27908351
- Full Text :
- https://doi.org/10.1016/j.jacc.2016.09.925