A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration

Makoto Natsumeda, Victoria Florea, Angela C. Rieger, Bryon A. Tompkins, Monisha N. Banerjee, Samuel Golpanian, Julia Fritsch, Ana Marie Landin, Nilesh Kashikar, Vasileios Karantalis, Viky Y. Loescher, Kostas E. Hatzistergos, Luiza Bagno, Cristina Sanina, Muzammil Mushtaq, Jose Rodriguez, Marcos Rosado, Ariel Wolf, Kevin Collon, Louis VincentAnthony J. Kanelidis, Ivonne H Schulman, Raul Mitrani, Alan W. Heldman, Wayne E Balkan, Joshua Hare

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2504-2515
Number of pages12
JournalJournal of the American College of Cardiology
Volume70
Issue number20
DOIs
StatePublished - Nov 14 2017

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Cell- and Tissue-Based Therapy
Mesenchymal Stromal Cells
Regeneration
Stem Cells
Swine
Cardiomyopathies
Cardiac Myocytes
Cicatrix
Placebos
Regulatory T-Lymphocytes
Mitosis
Catheterization
Histones
Immune System
Necrosis
Magnetic Resonance Imaging
Blood Pressure
Pressure
Injections

Keywords

  • allogeneic
  • cardiac stem cell
  • ischemic cardiomyopathy
  • mesenchymal stem cell

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Natsumeda, M., Florea, V., Rieger, A. C., Tompkins, B. A., Banerjee, M. N., Golpanian, S., ... Hare, J. (2017). A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration. Journal of the American College of Cardiology, 70(20), 2504-2515. https://doi.org/10.1016/j.jacc.2017.09.036

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration. / Natsumeda, Makoto; Florea, Victoria; Rieger, Angela C.; Tompkins, Bryon A.; Banerjee, Monisha N.; Golpanian, Samuel; Fritsch, Julia; Landin, Ana Marie; Kashikar, Nilesh; 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 E; Hare, Joshua.

In: Journal of the American College of Cardiology, Vol. 70, No. 20, 14.11.2017, p. 2504-2515.

Research output: Contribution to journalArticle

Natsumeda, M, Florea, V, Rieger, AC, Tompkins, BA, Banerjee, MN, Golpanian, S, Fritsch, J, Landin, AM, Kashikar, N, Karantalis, V, Loescher, VY, Hatzistergos, KE, Bagno, L, Sanina, C, Mushtaq, M, Rodriguez, J, Rosado, M, Wolf, A, Collon, K, Vincent, L, Kanelidis, AJ, Schulman, IH, Mitrani, R, Heldman, AW, Balkan, WE & Hare, J 2017, 'A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration', Journal of the American College of Cardiology, vol. 70, no. 20, pp. 2504-2515. https://doi.org/10.1016/j.jacc.2017.09.036
Natsumeda M, Florea V, Rieger AC, Tompkins BA, Banerjee MN, Golpanian S et al. A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration. Journal of the American College of Cardiology. 2017 Nov 14;70(20):2504-2515. https://doi.org/10.1016/j.jacc.2017.09.036
Natsumeda, Makoto ; Florea, Victoria ; Rieger, Angela C. ; Tompkins, Bryon A. ; Banerjee, Monisha N. ; Golpanian, Samuel ; Fritsch, Julia ; Landin, Ana Marie ; Kashikar, Nilesh ; 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 E ; Hare, Joshua. / A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration. In: Journal of the American College of Cardiology. 2017 ; Vol. 70, No. 20. pp. 2504-2515.
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title = "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 G{\"o}ttingen 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",
author = "Makoto Natsumeda and Victoria Florea and Rieger, {Angela C.} and Tompkins, {Bryon A.} and Banerjee, {Monisha N.} and Samuel Golpanian and Julia Fritsch and Landin, {Ana Marie} and Nilesh Kashikar and Vasileios Karantalis and Loescher, {Viky Y.} and Hatzistergos, {Kostas E.} and Luiza Bagno and Cristina Sanina and Muzammil Mushtaq and Jose Rodriguez and Marcos Rosado and Ariel Wolf and Kevin Collon and Louis Vincent and Kanelidis, {Anthony J.} and Schulman, {Ivonne H} and Raul Mitrani and Heldman, {Alan W.} and Balkan, {Wayne E} and Joshua Hare",
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language = "English (US)",
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pages = "2504--2515",
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TY - JOUR

T1 - A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration

AU - Natsumeda, Makoto

AU - Florea, Victoria

AU - Rieger, Angela C.

AU - Tompkins, Bryon A.

AU - Banerjee, Monisha N.

AU - Golpanian, Samuel

AU - Fritsch, Julia

AU - Landin, Ana Marie

AU - Kashikar, Nilesh

AU - Karantalis, Vasileios

AU - Loescher, Viky Y.

AU - Hatzistergos, Kostas E.

AU - Bagno, Luiza

AU - Sanina, Cristina

AU - Mushtaq, Muzammil

AU - Rodriguez, Jose

AU - Rosado, Marcos

AU - Wolf, Ariel

AU - Collon, Kevin

AU - Vincent, Louis

AU - Kanelidis, Anthony J.

AU - Schulman, Ivonne H

AU - Mitrani, Raul

AU - Heldman, Alan W.

AU - Balkan, Wayne E

AU - Hare, Joshua

PY - 2017/11/14

Y1 - 2017/11/14

N2 - 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.

AB - 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.

KW - allogeneic

KW - cardiac stem cell

KW - ischemic cardiomyopathy

KW - mesenchymal stem cell

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