Stem Cell Research—Shattered After Fabrication Scandal—Needs to Rebuild, Says EHJ Editor

The editorial is entitled “Lessons from the Earthquake,” and it is the centerpiece of several letters in the European Heart Journal expounding on the future of stem cell research and regenerative medicine in light of widescale scientific fraud that shook the field in recent years.

That fraud is well known by now—Piero Anversa, MD, PhD, a former giant of stem cell research, was found to have falsified and/or fabricated data in more than 30 research papers—but the reverberations are still being felt today. In fact, at least one clinical trial, the National Heart, Lung, and Blood Institute’s CONCERT-HF, has been paused while researchers try to understand the implications.  

“Such an earthquake has rarely, if ever, shattered a research field,” writes EHJ Editor-in-Chief Thomas Lüscher, MD (Imperial College, London).

In the April 2019 issue, several researchers discuss the current state of stem cell research and regenerative medicine, which Lüscher explains is an attempt to “push the reset button” in light of the Anversa scandal. “There was a lot of hope, and to see all this was really terrible,” Lüscher told TCTMD. “I think it’s very important to restart the field because it has such a bad reputation. . . . We shouldn’t give up [stem cell research] right away, but to try understand what went wrong and what we can still believe today.” 

Retractions, Lawsuits, and Settlements 

Anversa had been at the forefront of cardiomyocyte regeneration research, publishing the first study showing that the bone marrow cells of mice contained stem cells, known as c-Kit+ cells, that could regenerate heart muscle. Those findings, which really shook the field of cardiovascular regenerative medicine, could not be replicated over a period of several years and eventually the house of cards collapsed. Anversa left Harvard Medical School and the Brigham and Women’s Hospital, where he was the director of the Center for Regenerative Medicine, in 2015 after several papers were flagged and retracted.

In 2017, Partners Healthcare and Brigham and Women’s Hospital agreed to pay the United States government $10 million to settle allegations that Anversa, along with lab partners Annarosa Leri, MD, and Jan Kajstura, MD, fraudulently obtained funding from the National Institutes of Health (NIH). In 2018, an investigative committee from Harvard Medical School stated that the results from 31 papers published by the Anversa laboratory could not be trusted and recommended that they be retracted. More than a dozen of these papers have since been yanked by various journals, including the Lancet, New England Journal of Medicine, Circulation, and Circulation Research.

As part of the EHJ series, Darryl Davis, MD (University of Ottawa, Canada), highlights the status of cardiac stem cells in the post-Anversa era. The discovery that cardiac c-Kit+ cells were capable of self-renewal was established by Anversa’s laboratory. Given what’s transpired, “much of the literature supporting resident (in situ) c-Kit+ cells having any role in cardiac repair is open to question,” writes Davis.

Speaking with TCTMD, Davis said the unraveling of Anversa’s research for the past several years was an early warning that something was wrong, but the extent of academic malfeasance was a shock. He explained that cell types being studied today are either cultured from myocardial tissue after the identification of surface markers, such as c-Kit+ cells, or are derived from a mixed-cell product, such as cardiosphere-derived cells (CDC), before expansion to a clinical dose. Any research depending on c-Kit+ cells is now getting a second look.

The paused CONCERT-HF trial, for example, is testing two different forms of stem cell therapy, all delivered by transendocardial injection: mesenchymal stem cells, c-Kit+ cells, or a combination of these two cell lines, or placebo in patients with ischemic heart failure, documented coronary artery disease, and evidence of myocardial injury, LV dysfunction, and symptoms of heart failure.

“We don’t know a lot about what’s happening with the NIH trial,” said Davis. “There may not be a lot of enthusiasm to go back and explore c-Kit+ cells any more because there are other alternatives proven to be viable and that have already been tested in an extensive number of clinical trials.”

There are a series of comparative studies showing the c-Kit+ cells are functionally inferior to CDCs, he noted. To date, more than 45 labs have tested CDCs and shown the cells improve heart function when delivered after injury. “The c-Kit+ cells have only been tested in six labs, and in the head-to-head studies the c-Kit+ cells work but they’re just not as good as the cardiosphere-derived cells,” said Davis.

Heart Regenerates a Little Bit Each Year  

To TCTMD, Lüscher said researchers and journal editors should bring a healthy skepticism to promising new research. For example, at the American Heart Association 2011 Scientific Session in Los Angeles, five late-breaking clinical trials involving cardiac stem cells were presented. POSEIDON, TIME, ALCADIA, and SWISS-AMI, which tested different cell types (allogeneic mesenchymal stem cells, autologous human cardiac-derived stem cells, and bone-marrow mononuclear cells), and showed minimal, if any, benefit.

“And then comes SCIPIO,” said Lüscher, noting the trial showed a dramatic increase in left ventricular ejection fraction unmatched by any other study. The Lancet published SCIPIO, even though the study included 23 patients, but that study has since been retracted as part of the investigation into Anversa’s research. “As an editor, we have to be careful,” continued Lüscher. “There is fashion in science and we want to be the first. This is something that has been a lesson. When things look too good, we need to be more critical in the future.”

Olaf Bergmann, MD, PhD (Technische Universität, Dresden, Germany), notes that for the past two decades, there has been intensive interest in cell replacement therapy for heart diseases, an interest that was based on initial findings the myocardium could be regenerated by progenitor cells found in the heart or bone marrow. “Today, we know that bone marrow cells cannot differentiate into cardiomyocytes under physiological conditions, and if they do it all, resident cardiac progenitor cells only contribute to new cardiomyocytes with an insignificant biological relevance,” he writes.

Still, Bergmann and colleagues have shown that human cardiomyocytes renew “at a low, but detectable, rate of around 1% per year in young individuals” and less than 0.5% per year in older individuals. Although this rate of renewal is low, about 40% of the cardiomyocytes in a healthy heart is exchanged over the individual’s lifespan, suggesting that this renewal is necessary for maintenance of a normal heart. Bergmann also points to studies by Jeffrey Molkentin, PhD (University of Cincinnati, OH), that showed c-Kit+ cells are not the source of these new cardiomyocytes.

Given the evidence that the human heart regenerates new cardiomyocytes at a low annual rate, Bergmann says it may be possible to “augment this process in injured and diseased hearts to generate new myocardia, thereby improving cardiac function.”

Whatever the ongoing research shows, Lüscher said the Anversa scandal should remind the next-generation of researchers, the fellows in training, not to get caught in the rat race chasing positive results in their quest to publish. “If the experiments tell you something you didn’t anticipate,” he said. “You probably have [the results] right.”