ABOVE: In a mouse heart, injected stem cells (dashed lines showing injection site) recruit inflammatory (red) and non-inflammatory, healing (green) macrophages to elicit wound repair.

Injections of stem cells—either a patient’s own or from a donor—into the hearts of people with cardiac conditions has been shown in some cases to improve heart function. How the cells help has been a mystery. A paper in Nature today (November 27) shows that activation of an innate immune response can explain, and even recapitulate, the beneficial effects of stem cell transplants in the hearts of mice.

The findings suggest stem cells may not be required to boost cardiac repair, but some researchers argue that, by finally providing a mechanistic explanation, the study supports the use of cell therapy.

“This work is paradigm-shifting because it demonstrates a mechanism to explain a perplexing phenomenon that has intrigued cardiologists as a result of...

The idea of applying stem cells, derived from the bone marrow or elsewhere, to the heart to fix damage caused by myocardial infarction or cardiovascular disease has been the subject of intense pre-clinical and clinical investigations for the best part of two decades, and yet the field is highly controversial. Aside from the retractions of fraudulent papers that misguided the larger heart regeneration community for years, the observed benefits of cell transplant therapies are generally modest and, because the underlying mechanism of repair is unknown, there is a lack of consensus about which of the many types of stem cells and delivery approaches might work best, as well as which types of patients may benefit.

A better knowledge of the mechanism would drive better clinical trial design, says Jeffery Molkentin, a cardiovascular biologist at Cincinnati Children's Hospital Medical Center who led the latest project. Indeed, he says, if mechanistic studies had been done up-front then “we would have been much further along in the clinical trials [at this point].”

See “Hearts on Trial”

For transplanted cells to produce functional benefits in the heart, it’s likely the cells would need to remain there after injection. So Molkentin’s team studied a variety of stem cell types injected into mice “to see if any of them ever engrafted in the heart,” he says. “We had a list of five of the most prominent ones and none of the five ever engrafted, and they were all cleared within less than two weeks and sometimes within five or six days.” But, the team did spot something else happening. “In all [cases],” he says, “there was this really noticeable inflammatory response.”

The team then showed that whether they injected live stem cells, dead stem cells, or zymosan—a potent activator of the innate immune system—into the hearts of mice that had been given an experimental myocardial infarction, functional improvement of the heart occurred. By contrast, an injection of cyclosporine—which suppresses the innate immune system—after the cell delivery eliminated the beneficial effects.

The team went on to show that in the injured hearts of mice that received cell therapy or zymosan treatment there was evidence of improved muscle mechanical properties as well as scar remodeling and reduction. Both treatments recruited certain subtypes of macrophages that experiments indicated were driving this remodeling.

A heart attack triggers innate immunity automatically, prompting the essential scarring without which the heart would rupture, says Molkentin. The cell therapy (or zymosan treatment), being delayed by one week, does not exacerbate this initial inflammation, he says, but instead somehow “realigns the healing process and makes for a better scar.”

“It seems like it optimize[s] the properties of the area around the scar and the contractility of that area,” Molkentin says, “but we don’t know exactly why yet. . . . We’re trying to figure this out.”

Whatever the precise mechanism, the study “shows the importance of the immune system,” says Paul Riley of the University of Oxford who studies regenerative medicine but was not involved in the research. “It’s certainly very important for the field to be aware of this [finding],” he continues. “It will stimulate further interest in targeting or modulating, or thinking about the way the immune response . . . can effect more optimal function and repair after acute myocardial infarction.”

If the results hold true in humans, it could have implications for any future trials in which patients might receive immunosuppression to prevent cell rejection, suggests Riley. Although it’s not thought any such trials are currently underway, according to Molkentin and Joshua Hare, a cardiologist and stem cell researcher at the University of Miami who was not involved in the study, if embryonic stem cells were ever approved for trial “they would require immunosuppressives,” Hare says.

Hare has been involved in a number of stem cell therapy trials and sees the paper not as evidence that the stem cells themselves aren’t necessary, but instead as a mechanistic explanation for the fact that they do work. It is often the case in medicine, he says, that once a treatment is in use, “we change our perspective on how they work.” Fundamentally, he says, “we know that the cells are working,” and that they’re safe. He therefore thinks the paper “supports the field and . . . substantiates that we were on the right track.” That said, he adds, “If someone takes these findings and comes up with a better approach, a safer approach, a more efficacious approach, that’s great.”

R.J. Vagnozzi et al., “An acute immune response underlies the benefit of cardiac stem-cell therapy,” Nature, doi:10.1038/s41586-019-1802-2, 2019.

Ruth Williams is a freelance journalist based in Connecticut. Email her at ruth@wordsbyruth.com or find her on Twitter @rooph.

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