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A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration.

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.

journal_name

J Am Coll Cardiol

journal_title

Journal of the American College of Cardiology

authors

Natsumeda M,Florea V,Rieger AC,Tompkins BA,Banerjee MN,Golpanian S,Fritsch J,Landin AM,Kashikar ND,Karantalis V,Loescher VY,Hatzistergos KE,Bagno L,Sanina C,Mushtaq M,Rodriguez J,Rosado M,Wolf A,Collon K,Vincent L,

doi

10.1016/j.jacc.2017.09.036

subject

Has Abstract

pub_date

2017-11-14 00:00:00

pages

2504-2515

issue

eissn

0735-1097

issn

1558-3597

pii

S0735-1097(17)39823-6

journal_volume

pub_type

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A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration.