In this microscopic histology image, macrophage immune cells (shown in red and green) flock to the injured region of a damaged mouse heart three days after researchers injected adult heart stem cells within the yellow dotted area. Researchers report Nov. 27, 2019 in Nature that stem cell therapy helps hearts recover from heart attack by triggering an innate immune response that alters cell activity around the injured area so that it heals with a more optimized scar and improved contractile properties. Credit: Cincinnati Children’s Hospital Medical Center

A study published in the Nov. 27, 2019, advance online issue of Nature manages a rare feat. It is both a vindication of and egg in the face for cardiac stem cell research. 

The good news is that cardiac stem cell transplantation after a heart attack does improve heart function, although the effect is “mild,” Jeffery Molkentin told BioWorld.  

The bad news is that there is nothing about their stemness that makes the cells work.  

“There is no magic stem cell,” Molkentin said. “You could inject dead cell debris” – which, in fact, he and his team did at one point in their experiments.  

Molkentin is executive co-director of the Heart Institute at Cincinnati Children’s Hospital Medical Center, a Howard Hughes Investigator, and the senior author of the paper, whose title sums up its findings rather succinctly: “An acute immune response underlies the benefits of cardiac stem-cell therapy.” 

The work began as an attempt to shed light on conflicting reports of how to get maximal benefit, or indeed any benefit at all, from cardiac stem cell transplantation.  

Reports on whether injecting stem cells could help repair adult hearts have varied, though the weight of the evidence has suggested that there is a benefit. 

The molecular mechanism underlying that benefit, though, has been unclear. Initially, the idea was that the injected cells homed to damaged tissue and differentiated into heart muscle cells. But plenty of attempts yielded only weak and conflicting evidence for such integration. The current favored hypothesis is that the injected cells work via a paracrine mechanism, secreting factors that help damaged heart muscle cells recover. 

In the meantime, clinical trials “progressed without really a true understanding of what the basic science was,” Molkentin said.  

Legitimate trials involved several thousand patients and, as in other areas of stem cell medicine, there is a parallel universe of quacks only too happy to cater to the hopes of desperate patients, for a price. 

Jeffery Molkentin, executive co-director, Heart Institute at Cincinnati Children’s Hospital Medical Center

As both a cause and an effect of that lack of understanding, cardiac repair experiments have been done with a number of different cells. Molkentin said that there is “really no uniformity” to even the definition of stem cell. As a result, more than a dozen different cell types have been used in transplantation experiments, and “all of them are claimed in their respective papers to be the magic cells – the best for the patients.” 

Molkentin and his colleagues began their work by directly comparing five different stem cell types for cardiac repair after experimentally induced heart attacks in mice. 

Those experiments revealed that those cells “all worked the same, none of them worked differently, and all of them [were] cleared” without integrating into the heart.  

“But what we did notice,” he added, “was that the cells were dying.” 

That first alerted the investigators that the benefit of stem cells might come from setting off inflammation. 

Further experiments

Though chronic inflammation is a major contributor to disease, acute inflammation is a helpful phenomenon. 

“With any acute injury… without an inflammatory response, healing does not occur correctly, and sometimes not at all,” Molkentin explained. Clinical studies have shown that shutting down inflammation in heart attack patients will increase their risk of dying. 

“You need this goldilocks-like idea of inflammation,” he said. “A little bit, and not too long.” 

Another round of experiments confirmed that a localized, acute innate immune response was the underlying cause of better healing in mice that received transplants. 

Dead cells and a Toll-like receptor agonist were as effective as living stem cells in improving cardiac repair, while shutting down the immune system during treatment prevented any such benefit from occurring. 

Molkentin and his colleagues also showed that the specific immune cells involved were CX3CR1-expressing macrophages, which flocked to the injured area and “altered cardiac fibroblast activity, reduced border zone extracellular matrix (ECM) content, and enhanced the mechanical properties of the injured area,” the authors wrote in their paper.  

Robert Simari, executive vice chancellor, executive dean, and Franklin E. Murphy professor of cardiology at Kansas University Medical School, said that the mechanisms proposed by Molkentin are “absolutely fascinating. … If the mechanism is as proposed, we and others in the field are going to be able to learn from that.”  

“I’m really glad that someone of his stature continued to try to pursue the adult stem cell field and try to bring some clarity into the mechanism,” Simari told BioWorld. “I’m also glad that he demonstrated that there were positive effects in the animal models,” given that clinical results to date have been “very mixed, if not more negative.” 

Simari has conducted multiple cardiovascular stem cell trials. He is currently the study chair of two trials by the cardiovascular cell therapy research network (CCTRN), SENECA and CONCERT-HF. CONCERT-HF is testing the use of c-kit-positive cardiac stem cells, one of the cell types investigated by Molkentin and his team, in heart failure patients. 

Molkentin and colleagues plan to dig into whether specifically activating beneficial macrophages via pharmacological approaches could replicate the benefits of stem cell transplantation. 

Molkentin was somewhere between agnostic and skeptical of continuing attempts at stem cell transplantation for cardiac repair itself. 

The method is effective, he acknowledged, but “it doesn’t work great, it’s not a huge effect… You need a lot of mice to see it.” 

And the work implies that for that effect to occur, it will be necessary to inject cells directly into the heart rather than the vasculature, as the majority of trials has done, with its attendant safety issues.  

“This is a pretty elaborate treatment, to go and inject [cells] into a beating heart,” he said. “Is that worth it? That’s a question.”  

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