A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration

• Published in: Journal of the American College of Cardiology 2017-11, Vol.70 (20), p.2504-2515
• Main Authors: Natsumeda, Makoto, Florea, Victoria, Rieger, Angela C., Tompkins, Bryon A., Banerjee, Monisha N., Golpanian, Samuel, Fritsch, Julia, Landin, Ana Marie, Kashikar, Nilesh D., Karantalis, Vasileios, Loescher, Viky Y., Hatzistergos, Kostas E., Bagno, Luiza, Sanina, Cristina, Mushtaq, Muzammil, Rodriguez, Jose, Rosado, Marcos, Wolf, Ariel, Collon, Kevin, Vincent, Louis, Kanelidis, Anthony J., Schulman, Ivonne H., Mitrani, Raul, Heldman, Alan W., Balkan, Wayne, Hare, Joshua M.
• Format: Article
• Language: English
• Subjects: allogeneic; Animals; Autografts; Blood pressure; Bone marrow; cardiac stem cell; Cardiology; Cardiomyocytes; Cardiomyopathy; Catheterization; CD25 antigen; CD3 antigen; Clinical trials; Diabetes; Disease Models, Animal; Female; Foxp3 protein; Heart; Heart attacks; Heart diseases; Heart failure; Heart Ventricles - diagnostic imaging; Heart Ventricles - physiopathology; Histone H3; Hogs; Immune response; Immune system; Immunoregulation; Inflammation; Injections; Ischemia; ischemic cardiomyopathy; Kinases; Livestock; Lymphocytes; Lymphocytes T; Magnetic resonance imaging; Magnetic Resonance Imaging, Cine; Mercury; mesenchymal stem cell; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stem Cells - cytology; Mesenchyme; Mitosis; Myocardial Ischemia - diagnosis; Myocardial Ischemia - physiopathology; Myocardial Ischemia - therapy; Myocardium; Recovery of function; Regeneration; Rodents; Skin & tissue grafts; Stem cell transplantation; Stem cells; Swine; Synergistic effect; Systolic pressure; Transplantation, Homologous; Transplants & implants; Ventricle; Ventricular Remodeling
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2017.09.036

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