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An acute immune response underlies the benefit of cardiac adult stem cell therapy

Ronald J. Vagnozzi, Marjorie Maillet, Michelle A. Sargent, Hadi Khalil, Anne Katrine Johansen, Jennifer A. Schwanekamp, Allen J. York, Vincent Huang, Matthias Nahrendorf, Sakthivel Sadayappan, View ORCID ProfileJeffery D. Molkentin
doi: https://doi.org/10.1101/506626
Ronald J. Vagnozzi
1Department of Pediatrics, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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Marjorie Maillet
1Department of Pediatrics, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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Michelle A. Sargent
1Department of Pediatrics, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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Hadi Khalil
1Department of Pediatrics, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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Anne Katrine Johansen
1Department of Pediatrics, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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Jennifer A. Schwanekamp
2Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati, Cincinnati, OH, USA
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Allen J. York
1Department of Pediatrics, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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Vincent Huang
1Department of Pediatrics, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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Matthias Nahrendorf
3Center for Systems Biology, Department of Imaging, and Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Sakthivel Sadayappan
2Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati, Cincinnati, OH, USA
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Jeffery D. Molkentin
1Department of Pediatrics, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
4Howard Hughes Medical Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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  • ORCID record for Jeffery D. Molkentin
  • For correspondence: jeff.molkentin@cchmc.org
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Abstract

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day1–3 despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biologic effect4–6. The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischemic injury7–9. Here we examined the mechanistic basis for cell therapy in mice after ischemia/reperfusion (I/R) injury, and while heart function was enhanced, it was not associated with new cardiomyocyte production. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2+ and CX3CR1+ macrophages. Here we observed that intra-cardiac injection of 2 distinct types of progenitor cells, freeze/thaw-killed cells or a chemical inducer of the innate immune response similarly induced regional CCR2+ and CX3CR1+ macrophage accumulation and provided functional rejuvenation to the I/R-injured heart. Mechanistically, this selective macrophage response altered cardiac fibroblast activity and reduced border zone extracellular matrix (ECM) content and enhanced the mechanical properties of the injured area. The functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound healing response that rejuvenates the mechanical properties of the infarcted area of the heart. Such results suggest a re-evaluation of strategies underlying cardiac cell therapy in current and planned human clinical trials.

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Posted December 26, 2018.
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An acute immune response underlies the benefit of cardiac adult stem cell therapy
Ronald J. Vagnozzi, Marjorie Maillet, Michelle A. Sargent, Hadi Khalil, Anne Katrine Johansen, Jennifer A. Schwanekamp, Allen J. York, Vincent Huang, Matthias Nahrendorf, Sakthivel Sadayappan, Jeffery D. Molkentin
bioRxiv 506626; doi: https://doi.org/10.1101/506626
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An acute immune response underlies the benefit of cardiac adult stem cell therapy
Ronald J. Vagnozzi, Marjorie Maillet, Michelle A. Sargent, Hadi Khalil, Anne Katrine Johansen, Jennifer A. Schwanekamp, Allen J. York, Vincent Huang, Matthias Nahrendorf, Sakthivel Sadayappan, Jeffery D. Molkentin
bioRxiv 506626; doi: https://doi.org/10.1101/506626

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