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J Am Coll Cardiol. 2016 Dec 6;68(22):2454-2464. doi: 10.1016/j.jacc.2016.09.925.

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

Author information

1
The Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida.
2
Biology Department and Integrated Regenerative Research Institute, San Diego State University, San Diego, California.
3
Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida.
4
The Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida; Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida.
5
The Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine, Miami, Florida; Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida. Electronic address: jhare@med.miami.edu.

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 < 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).

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.

KEYWORDS:

heart failure; human cardiac progenitor cells; injection; pressure volume

PMID:
27908351
PMCID:
PMC5223744
DOI:
10.1016/j.jacc.2016.09.925
[Indexed for MEDLINE]
Free PMC Article

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