For nearly two decades, Dr. Chuck Murry, a University of Washington cardiovascular biology researcher, has been intent on transforming powerful human stem cells into heart-muscle cells that can repair damaged hearts.
He and his colleagues have worked through myriad setbacks and complications in studies on mice, rats and guinea pigs, piling up successes as their animal models got larger and physiologically closer to humans.
Now, in a bold step toward ultimately being able to stem the tide of heart failure in humans with damaged hearts, they have successfully regenerated heart muscle in monkeys, Murry, Dr. Michael Laflamme and his UW colleagues reported in the journal Nature on Wednesday.
As before, researchers at the UW Institute for Stem Cell and Regenerative Medicine transformed human stem cells into heart-muscle cells — this time injecting them into the damaged hearts of monkeys. There, the cells assembled themselves into muscle fibers, began beating in the heart’s rhythm, and ultimately were nurtured by the monkeys’ arteries and veins, which grew into the new heart tissue.
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On average, the transplanted cells regenerated 40 percent of the damaged areas.
“This is 10 times more heart muscle than anybody else in the world has been able to generate,” said Murry, who predicted his lab would be ready for clinical trials in humans within four years.
The Murry team’s latest success, like the others, had its own complications, but even so, cardiovascular-research leaders not connected with the work hailed it as a significant advance.
Dr. Michael Simons, director of the Yale Cardiovascular Research Center, said the research is the first to show that human embryonic stem cells can fully integrate into normal heart tissue. The lab’s impressive ability to “scale up” production of sufficient newly programmed stem cells for a large-animal heart closer to the size of a human heart, which was done by Laflamme’s team, was likely unprecedented, as well.
“It’s a very big deal,” said Dr. Richard Lee of the Harvard Stem Cell Institute and Brigham and Women’s Hospital in Boston.
Murry is “an extraordinarily careful and thoughtful investigator,” Lee said. “When work comes out of his lab it makes us all feel better because we know we can trust it.”
Heart-muscle damage, typically caused by a heart attack, leads to heart failure, which for Murry is Public Enemy No. 1, with less average survival time than breast cancer, he said. When a heart attack damages heart muscle, it forms scar tissue rather than growing back.
If there is enough damage, the heart may not have enough muscle to pump out blood, leading to heart failure, which Murry calls “a burgeoning public-health problem.”
“It’s really bad now, and it’s going to get worse” as the baby-boomer generation ages, he said.
The most serious problem encountered in the research was a period of irregular heartbeats, known as arrhythmias. Although the monkeys’ arrhythmias disappeared after a few weeks, Murry and others said it was concerning.
Simons said arrhythmias are serious and can be deadly. They are also more likely to occur in this sort of intervention on a larger heart, he said.
“The question is: How serious are they? How long do they last? Do they go away after several weeks after the tissue matures and the heart matures, or is it a lifelong problem?”
Murry said if his lab hadn’t been monitoring the monkeys 24-7, researchers might have missed the arrhythmias, which didn’t appear to have disturbed the monkeys.
“The monkey is in the cage eating a banana,” Murry said. Meanwhile, “the investigators are freaking out. We’re having the heart attack.”
The six monkeys involved in the study were pigtail macaques, a type commonly used in research. The heart damage was created by the researchers, who induced controlled myocardial infarctions, a type of heart attack that in humans is typically caused by coronary artery disease.
As planned, to examine the heart tissue, researchers performed necropsies on the animals at various points in the study; the necropsy on the last monkey was done at three months. No tumors, an earlier concern with stem-cell grafts, were found in any of the animals.
The study, funded primarily by federal grants with additional private donations, used stem cells derived from a federally approved human embryonic stem-cell line. About 90 percent of the 1 billion stem cells injected into each monkey’s heart died, which Murry called “a sore point.”
The damaged area of the heart has problems with blood vessels and a lot of inflammation, Murry said. “It’s a harsh environment to put these cells — that’s why so many of them die.”
The new cells have to survive for nearly a week before they get any blood supply, he said. “It’s asking a lot.”
Over the years, the lab has improved cell survival by a factor of 100, but the cell death rate is still high. “Let’s call it an opportunity for self-improvement,” he said wryly.
This study, which Murry called “proof of concept” that stem cells can regenerate heart muscle, did not look at whether grafts strengthen the heart’s ability to pump blood. The team’s earlier studies using similar techniques in smaller animals did show improvement in the heart’s function, and there was some indication that was true for some of the monkeys.
For Murry, his lab’s latest success is bittersweet. His 86-year-old mother, Donna Murry — the inspiration and motivation for his focus on fixing damaged hearts, he said — died last week of multiple infarctions. Heart disease runs in the family, Murry said.
“She is the kind of person we would like to have helped,” he said. “My mom would have been so proud.”
Carol M. Ostrom: firstname.lastname@example.org or 206-464-2249. On Twitter @costrom