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J Am Coll Cardiol. 2017 Nov 14;70(20):2504-2515. doi: 10.1016/j.jacc.2017.09.036.

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration.

Author information

1
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
2
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.
3
Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida.
4
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
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
6
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:

The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT).

OBJECTIVES:

This study sought to test the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions.

METHODS:

Göttingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of allo-MSCs + allo-CSCs (ACCT: 200 million MSCs/1 million CSCs, n = 7), 200 million allo-MSCs (n = 8), 1 million allo-CSCs (n = 4), or placebo (Plasma-Lyte A, n = 6). Swine were assessed by cardiac magnetic resonance imaging and pressure volume catheterization. Immune response was tested by histologic analyses.

RESULTS:

Both ACCT and allo-MSCs reduced scar size by -11.1 ± 4.8% (p = 0.012) and -9.5 ± 4.8% (p = 0.047), respectively. Only ACCT, but not MSCs or CSCs, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure-volume relation (+0.98 ± 0.41 mm Hg/ml; p = 0.016). The ACCT group had more phospho-histone H3+ (a marker of mitosis) cardiomyocytes (p = 0.04), and noncardiomyocytes (p = 0.0002) than did the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC-treated swine contained immunotolerant CD3+/CD25+/FoxP3+ regulatory T cells (p < 0.0001). Histologic analysis showed absent to low-grade inflammatory infiltrates without cardiomyocyte necrosis.

CONCLUSIONS:

ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunologic reaction. Clinical translation to humans is warranted.

KEYWORDS:

allogeneic; cardiac stem cell; ischemic cardiomyopathy; mesenchymal stem cell

PMID:
29145950
PMCID:
PMC5796680
DOI:
10.1016/j.jacc.2017.09.036
[Indexed for MEDLINE]
Free PMC Article

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