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

Ronald J. Vagnozzi, Marjorie Maillet, Michelle A. Sargent, Hadi Khalil, Anne Katrine Z. Johansen, Jennifer A. Schwanekamp, Allen J. York, Vincent Huang, Matthias Nahrendorf, Sakthivel Sadayappan and Jeffery D. Molkentin ()
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Ronald J. Vagnozzi: University of Cincinnati, Cincinnati Children’s Hospital Medical Center
Marjorie Maillet: University of Cincinnati, Cincinnati Children’s Hospital Medical Center
Michelle A. Sargent: University of Cincinnati, Cincinnati Children’s Hospital Medical Center
Hadi Khalil: University of Cincinnati, Cincinnati Children’s Hospital Medical Center
Anne Katrine Z. Johansen: University of Cincinnati, Cincinnati Children’s Hospital Medical Center
Jennifer A. Schwanekamp: University of Cincinnati
Allen J. York: University of Cincinnati, Cincinnati Children’s Hospital Medical Center
Vincent Huang: University of Cincinnati, Cincinnati Children’s Hospital Medical Center
Matthias Nahrendorf: Massachusetts General Hospital of the Harvard Medical School
Sakthivel Sadayappan: University of Cincinnati
Jeffery D. Molkentin: University of Cincinnati, Cincinnati Children’s Hospital Medical Center

Nature, 2020, vol. 577, issue 7790, 405-409

Abstract: Abstract Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day1,2, despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect3. 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 ischaemic injury4,5. Here we examine the mechanistic basis for cell therapy in mice after ischaemia–reperfusion injury, and find that—although heart function is enhanced—it is not associated with the production of new cardiomyocytes. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2+ and CX3CR1+ macrophages. Intracardiac injection of two distinct types of adult stem cells, cells killed by freezing and thawing or a chemical inducer of the innate immune response all induced a similar regional accumulation of CCR2+ and CX3CR1+ macrophages, and provided functional rejuvenation to the heart after ischaemia–reperfusion injury. This selective macrophage response altered the activity of cardiac fibroblasts, reduced the extracellular matrix content in the border zone 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 infarcted area of the heart.

Date: 2020
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DOI: 10.1038/s41586-019-1802-2

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