A provocative new study calls into question the rationale for using stem cells to repair the heart — a much-hyped experimental therapy that grew out of insights from a groundbreaking Boston researcher’s laboratory.
The paper published Wednesday shows that these stem cells normally generate new cardiac muscle cells at a glacial rate in mice, and the authors said this suggests the stem cells alone would be unlikely to contribute significantly to regeneration of muscle in heart-disease patients.
“We just asked: Do the cells in the heart do this themselves? They’re in the heart, can they do it?” said Jeffery Molkentin, a cardiovascular molecular biologist at Cincinnati Children’s Heart Institute, who led the work published in the journal Nature. “The answer there is basically no.”
He said the findings raise questions about whether stem cells should be used to “fix the heart, and how might they be fixing the heart?”
The research is the latest salvo in the heart stem cell wars — and will further roil a deeply divided field that owes many of its foundational ideas to Dr. Piero Anversa, a Brigham and Women’s Hospital researcher whose laboratory is in the midst of a Harvard Medical School investigation that has found problems with data integrity in two of its papers. Anversa was already controversial because his results were often in conflict with those of other researchers in the field.
Many credit Anversa for the dogma-challenging insight that the heart has the capacity to regenerate itself. That broad notion is now accepted, but the field has since split into two camps over how — and how much — the heart regenerates. Figuring out how to harness that regenerative potential as a therapy depends on the answers.
For a number of outside scientists, the new work brings clarity: The heart can regenerate, but at a very low rate. That does not prove that the therapeutic approach being used in patients won’t work, but some said it raises serious questions about the value of cardiac stem cells — called c-kit cells after a protein that is used to identify them.
“It’s one more indication that it may be a house of cards — the theory of c-kit cardiac stem cells,” said Dr. Jonathan Epstein, a professor of cardiovascular research at the University of Pennsylvania Perelman School of Medicine. “Put in the context of a paper being retracted, and issues regarding reproducibility of findings, it’s one more reason to believe that pushing forward with clinical trials may not be sensible.”
Others noted that the new research didn’t test what’s done to treat patients — stem cells are removed, multiplied in lab dishes, and then infused back into patients.
“It would be utterly absurd to change plans regarding clinical trials of c-kit cardiac stem cells based on this one mouse study,” Dr. Roberto Bolli, director of the University of Louisville’s Institute of Molecular Cardiology, wrote in an e-mail. He emphasized that multiple animal studies suggest infusing c-kit stem cells into the heart is beneficial.
Bolli led an early-stage safety trial of infusing c-kit cells into the hearts of heart disease patients and found no adverse effects. The paper reporting the results of that study have now been flagged as a result of the Harvard investigation, however, because of data integrity problems with images in the paper created by Anversa’s laboratory. Harvard Medical School recently retracted another one of Anversa’s papers showing a high rate of renewal of heart muscle cells.
The debate over heart stem cells dates to 2001, when Anversa’s lab showed that bone marrow cells could be injected into an injured rodent heart to repair it. Several independent laboratories could not replicate the results, but the technique was tried — many think too hurriedly — in patients, first in Europe and then in the United States.
In 2003, Anversa’s laboratory published results suggesting that the heart had its own stem cells, the c-kit cells. For years, scientists have debated the role those cells play in regenerating heart muscle, with studies providing evidence for both sides.
The new paper used a method that genetically tags c-kit cells so that they glow green — as will any heart muscle cells created by those cells.
The scientists looked in newborn and adult mice, and injured mouse hearts and found only a tiny percentage of muscle cells glowed — three cells in 10,000.
Anversa said by e-mail that his own lab is working with the same technique, with results pending. He noted that given the rate of cell death that he has measured in the heart, regeneration must occur at a rapid rate — because without it, “the heart would barely exist.”
Supporters of using heart stem cells as therapy argue that whether the rate of regeneration is high or low doesn’t really matter. The important thing, they say, is that it happens at all.
But a leading stem cell scientist disagreed. “Low versus high is all the difference in the world to a patient who has a heart attack,” said Dr. Irving Weissman, director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University.
“If, over and over, only one lab is showing massive regeneration or massive incorporation of cells in the heart . . . then somebody who takes that forward to clinical therapies without really good evidence is risking the patients and themselves.”
Other c-kit stem cell clinical trials are in the planning stages. Dr. Joshua Hare of the University of Miami School of Medicine said that he has received FDA-approval for a trial that will combine two types of stem cells, including c-kit stem cells.
“The problem with the controversy is that some people say, ‘Wait a minute. Stop the trials’ because there’s a controversy. And that’s the wrong thing to do. The right thing to do is to design the best possible trials and conduct them,” Hare said.
Further complicating the field is the fact that it is rife with potential conflicts of interest. Eduardo Marban, director of Cedars-Sinai Heart Institute was a coauthor of the paper and provided external verification of the results in the new paper. His lab was sent specimens of heart to count the number of new cardiac muscle cells, and were blinded as to what the specimens were. Critics point out he has a company called Capricor that is trying to commercialize a different stem cell approach. Hare, in Miami, founded a company called Vestion Pharma that is focused on commercializing a combination of c-kit and another type of stem cells based on the insights from his laboratory.