Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy

Vasileios Karantalis, Viky Y. Suncion-Loescher, Luiza Bagno, Samuel Golpanian, Ariel Wolf, Cristina Sanina, Courtney Premer, Anthony J. Kanelidis, Frederic McCall, Bo Wang, Wayne E Balkan, Jose Rodriguez, Marcos Rosado, Azorides R Morales, Konstantinos Hatzistergos, Makoto Natsumeda, Irene Margitich, Ivonne H Schulman, Samirah A. Gomes, Muzammil MushtaqDarcy L. DiFede, Joel Fishman, Pradip Pattany, Juan Pablo Zambrano, Alan W. Heldman, Joshua Hare

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Background Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically. Objectives To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy. Methods Three months after ischemia/reperfusion injury, Göttingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy. Results Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs -44.1 ± 6.8%; CSC/MSC -37.2 ± 5.4%; placebo -12.9 ± 4.2%; p <0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 ± 1.6 EF units; CSC/MSC 6.9 ± 2.8 EF units; placebo 2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity. Conclusions These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.

Original languageEnglish (US)
Pages (from-to)1990-1999
Number of pages10
JournalJournal of the American College of Cardiology
Volume66
Issue number18
DOIs
StatePublished - Nov 3 2015

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Cell- and Tissue-Based Therapy
Mesenchymal Stromal Cells
Cardiomyopathies
Stem Cells
Placebos
Swine
Injections
Ventricular Remodeling
Reperfusion Injury
Cardiac Myocytes
Cardiac Output
Stroke Volume
Cicatrix
Myocardial Ischemia
Magnetic Resonance Spectroscopy
Heart Failure
Bone Marrow
Clinical Trials
Safety
Therapeutics

Keywords

  • cardiac
  • combination therapy
  • heart failure
  • mesenchymal stem cell

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy. / Karantalis, Vasileios; Suncion-Loescher, Viky Y.; Bagno, Luiza; Golpanian, Samuel; Wolf, Ariel; Sanina, Cristina; Premer, Courtney; Kanelidis, Anthony J.; McCall, Frederic; Wang, Bo; Balkan, Wayne E; Rodriguez, Jose; Rosado, Marcos; Morales, Azorides R; Hatzistergos, Konstantinos; Natsumeda, Makoto; Margitich, Irene; Schulman, Ivonne H; Gomes, Samirah A.; Mushtaq, Muzammil; DiFede, Darcy L.; Fishman, Joel; Pattany, Pradip; Zambrano, Juan Pablo; Heldman, Alan W.; Hare, Joshua.

In: Journal of the American College of Cardiology, Vol. 66, No. 18, 03.11.2015, p. 1990-1999.

Research output: Contribution to journalArticle

Karantalis, V, Suncion-Loescher, VY, Bagno, L, Golpanian, S, Wolf, A, Sanina, C, Premer, C, Kanelidis, AJ, McCall, F, Wang, B, Balkan, WE, Rodriguez, J, Rosado, M, Morales, AR, Hatzistergos, K, Natsumeda, M, Margitich, I, Schulman, IH, Gomes, SA, Mushtaq, M, DiFede, DL, Fishman, J, Pattany, P, Zambrano, JP, Heldman, AW & Hare, J 2015, 'Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy', Journal of the American College of Cardiology, vol. 66, no. 18, pp. 1990-1999. https://doi.org/10.1016/j.jacc.2015.08.879
Karantalis V, Suncion-Loescher VY, Bagno L, Golpanian S, Wolf A, Sanina C et al. Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy. Journal of the American College of Cardiology. 2015 Nov 3;66(18):1990-1999. https://doi.org/10.1016/j.jacc.2015.08.879
Karantalis, Vasileios ; Suncion-Loescher, Viky Y. ; Bagno, Luiza ; Golpanian, Samuel ; Wolf, Ariel ; Sanina, Cristina ; Premer, Courtney ; Kanelidis, Anthony J. ; McCall, Frederic ; Wang, Bo ; Balkan, Wayne E ; Rodriguez, Jose ; Rosado, Marcos ; Morales, Azorides R ; Hatzistergos, Konstantinos ; Natsumeda, Makoto ; Margitich, Irene ; Schulman, Ivonne H ; Gomes, Samirah A. ; Mushtaq, Muzammil ; DiFede, Darcy L. ; Fishman, Joel ; Pattany, Pradip ; Zambrano, Juan Pablo ; Heldman, Alan W. ; Hare, Joshua. / Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy. In: Journal of the American College of Cardiology. 2015 ; Vol. 66, No. 18. pp. 1990-1999.
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abstract = "Background Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically. Objectives To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy. Methods Three months after ischemia/reperfusion injury, G{\"o}ttingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy. Results Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs -44.1 ± 6.8{\%}; CSC/MSC -37.2 ± 5.4{\%}; placebo -12.9 ± 4.2{\%}; p <0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 ± 1.6 EF units; CSC/MSC 6.9 ± 2.8 EF units; placebo 2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity. Conclusions These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.",
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T1 - Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy

AU - Karantalis, Vasileios

AU - Suncion-Loescher, Viky Y.

AU - Bagno, Luiza

AU - Golpanian, Samuel

AU - Wolf, Ariel

AU - Sanina, Cristina

AU - Premer, Courtney

AU - Kanelidis, Anthony J.

AU - McCall, Frederic

AU - Wang, Bo

AU - Balkan, Wayne E

AU - Rodriguez, Jose

AU - Rosado, Marcos

AU - Morales, Azorides R

AU - Hatzistergos, Konstantinos

AU - Natsumeda, Makoto

AU - Margitich, Irene

AU - Schulman, Ivonne H

AU - Gomes, Samirah A.

AU - Mushtaq, Muzammil

AU - DiFede, Darcy L.

AU - Fishman, Joel

AU - Pattany, Pradip

AU - Zambrano, Juan Pablo

AU - Heldman, Alan W.

AU - Hare, Joshua

PY - 2015/11/3

Y1 - 2015/11/3

N2 - Background Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically. Objectives To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy. Methods Three months after ischemia/reperfusion injury, Göttingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy. Results Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs -44.1 ± 6.8%; CSC/MSC -37.2 ± 5.4%; placebo -12.9 ± 4.2%; p <0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 ± 1.6 EF units; CSC/MSC 6.9 ± 2.8 EF units; placebo 2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity. Conclusions These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.

AB - Background Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically. Objectives To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy. Methods Three months after ischemia/reperfusion injury, Göttingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy. Results Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs -44.1 ± 6.8%; CSC/MSC -37.2 ± 5.4%; placebo -12.9 ± 4.2%; p <0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 ± 1.6 EF units; CSC/MSC 6.9 ± 2.8 EF units; placebo 2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity. Conclusions These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.

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