Modifying immune response can improve cardiac adult stem cell therapy

Significance 

A new study suggests the benefits of adult stem cell therapy to heal heart tissue after a heart attack are directly due to a modified immune response, not the injected cells themselves.

Cell therapies involve the injection of adult stem cells, often derived from bone marrow or heart tissue, following an infarct. Originally thought to generate new cardiomyocytes, studies and clinical trials using cell therapies since the early 2000s haven’t shown much evidence of this, but have nevertheless shown evidence of a modest improvement in heart function following a heart attack.

In their recently published paper in Nature, Jeffery Molkentin, MD, director of molecular cardiovascular biology at the Cincinnati Children’s Hospital Medical Center and Howard Hughes Medical Institute and his colleagues employed an array of strategies to conclusively isolate the cause of that modest improvement seen in cell therapy studies.

Utilizing injections of two types of adult stem cells—fractionated bone marrow mononuclear cells and cardiac progenitor cells—in post-ischemic injury mice, they not only found the reported improvements in heart function could be blocked by co-administration of the immunosuppressant drug cyclosporin A, but that the improvement could also be elicited by injecting an immuno-stimulant drug, zymosan, alone, without injecting cells. The zymosan in fact produced a slightly better improvement than did the cell therapies, Molkentin says, suggesting that cells in “cell therapy” clinical trials are not really what those trials should have been about. “We didn’t understand the mechanism of action. It was presumed that they would make new cardiomyocytes but that never happened,” he adds. “So the whole premise for all these clinical trials in humans is basically unfounded.”

Instead, Molkentin says, it appears that injecting cells is just one way to trigger an acute innate immune response that modifies the healing response of heart tissue after an injury. “After a myocardial infarction, there’s a window of time when the scar sets up and then everything aligns and there’s fibrosis and the remaining area of myocardium can be remodeled in a specific way,” he says. Injecting cells or the right immunostimulant during this window of time can “reinitiate a healing response with a selective type of macrophage activity that appears to benefit the mechanical properties of that scar.”

And that macrophage activity appears to be key to the pro-healing effect in cell therapies and zymosan treatment, according to Molkentin, both of which increased the activity of CX3CR1+ macrophages in particular. When they selectively inhibited macrophages, leaving the rest of the immune system intact, “that blocked the pro-rejuvenating like effect of cell therapy injection,” he adds.

To test the idea that the injected cells were actively secreting some factor or signal, Molkentin and his colleagues injected dead, fragmented cells post-infarct, and found these too stimulated an immune response and improved heart function.

The paper suggests a path forward focusing not on stem cell types, but on modifying and extending the innate immune response they’ve now identified as being behind the benefits of MNC- and CPC-based cell therapies.

Modifying immune response can improve cardiac adult stem cell therapy - Medicine Innovates

About the author

Jeffery D. Molkentin, PhD, is a professor in the Department of Pediatrics at the University of Cincinnati and Cincinnati Children’s Hospital Medical Center. He received his BS from Marquette University in Milwaukee Wisconsin (USA) in 1989. He then received his PhD from the Medical College of Wisconsin in 1994, after which he performed postdoctoral training with Dr. Eric Olson in Texas (USA) from 1994-1997, followed by his first faculty appointment in 1997 at the Cincinnati Children’s Hospital Medical Center of the University of Cincinnati (USA).

Dr. Molkentin has published over 400 original articles during this time, he has a Scopus H-index of 111. Dr. Molkentin was a Pew Scholar early in his career and is now a full investigator of the Howard Hughes Medical Institute in the USA since 2008. He has also won several awards such as the Louis N and Arnold M Katz award to young investigators and more recently the Basic Research Prize, both of the American Heart Association.

Dr. Molkentin also won the Lucian Award from McGill University. He has also served on NIH study section and was an organizer of various national and international scientific meetings. Finally, Dr Molkentin has placed 35 of his past trainees into academics as laboratory principle investigators. Dr. Molkentin’s research program continues to focus on the identification of candidate genes and signaling pathways involved in cardiac hypertrophy, contractility, cell death, heart failure, fibrosis, regeneration and muscular dystrophy, as well as mitochondria-dependent necrosis.

Reference

Vagnozzi RJ, Maillet M, Sargent MA, Khalil H, Johansen AKZ, Schwanekamp JA, York AJ, Huang V, Nahrendorf M, Sadayappan S, Molkentin JD. An acute immune response underlies the benefit of cardiac stem cell therapy. Nature. 2020 Jan;577(7790):405-409. doi: 10.1038/s41586-019-1802-2. Epub 2019 Nov 27.

Go To Nature 

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