RT Journal Article
SR Electronic
T1 An acute immune response underlies the benefit of cardiac adult stem cell therapy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 506626
DO 10.1101/506626
A1 Ronald J. Vagnozzi
A1 Marjorie Maillet
A1 Michelle A. Sargent
A1 Hadi Khalil
A1 Anne Katrine Johansen
A1 Jennifer A. Schwanekamp
A1 Allen J. York
A1 Vincent Huang
A1 Matthias Nahrendorf
A1 Sakthivel Sadayappan
A1 Jeffery D. Molkentin
YR 2018
UL http://biorxiv.org/content/early/2018/12/26/506626.abstract
AB 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.