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Nature. 2019 Nov 27. doi: 10.1038/s41586-019-1802-2. [Epub ahead of print]

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

Author information

1
Department of Pediatrics, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
2
Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati, Cincinnati, OH, USA.
3
Center for Systems Biology, Department of Imaging, and Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
4
Department of Pediatrics, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. jeff.molkentin@cchmc.org.
5
Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. jeff.molkentin@cchmc.org.

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 biologic 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 ischemic injury4,5. 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. Intra-cardiac injection of 2 distinct types of adult stem 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. This selective macrophage response altered cardiac fibroblast activity, 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.

PMID:
31775156
DOI:
10.1038/s41586-019-1802-2

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