Modifying immune response can improve cardiac adult stem cell therapy

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.