How to Fix a Damaged Heart
How do you mend a broken heart? For the zebrafish, an aquarium dweller with bright stripes down its side, it just takes time. Clip off a piece of its heart, says Gordon Keller, director of the McEwen Centre for Regenerative Medicine in Toronto, and it will eventually repair itself. "Why can the fish do it," he wonders, "and we can't?" Maybe, one day, that could change.
After a heart attack, a scar is left behind, distorting pumping action, "which can result, eventually, in heart failure," says Ottawa cardiologist Dr. Andreas Wielgosz, spokesperson for the Heart & Stroke Foundation of Canada. Cardiovascular disease is the No. 1 killer in Canada - yet cell-based therapies are offering new hope for treating damaged organs. Using the body's own building blocks, researchers are attempting to coax the human heart into generating functioning tissue where a scar would otherwise be.
Last year, Keller's team at the McEwen Centre became the first in the world to successfully grow human heart progenitor cells (immature heart cells) from embryonic stem cells. When allowed to mature, these cells give rise to functional heart cells that can actually be seen pulsing in a petri dish. "It's really reaching out to the cutting edge, to say we can regenerate heart tissue," Keller says. "But given we can make human heart cells, we have, for the first time, the ability to test this hypothesis." Embryonic stem cells aren't the only type that can be used to make heart cells. Keller's team is now creating them from a patient's adult cells (taken from a skin biopsy) which have been genetically reprogrammed to an embryonic-like state.
As the building blocks of the human heart, their potential to heal seems enormous - but how to use them in the clinic? Injecting lab-grown heart cells directly into the organ is one technique being tested in animal models, Keller says, but for reasons that aren't entirely understood, "the heart is hostile to transplanted cells. Most of them die." Seeding cells onto a scaffold that could be grafted onto the heart, like a living Band-Aid, might be a better option. Still, many hurdles remain: creating enough heart cells to build such a patch is a challenge, as is ensuring it would integrate electrically, and mechanically, with the heart, says Peter Zandstra, a bioengineer at the McEwen Centre and the University of Toronto. He's working on engineering heart tissue in the lab, as well as new techniques to create large numbers of cells, in the hope of creating patches that could one day be tested in animals.
McEwen researchers aren't the only Canadian group looking at cell transplantation. At the Ottawa Health Research Institute (OHRI), a team led by Dr. Duncan Stewart is set to begin the first-ever trial of an engineered cell therapy for HEART DISEASE. Stem-like cells will be harvested from the blood of roughly 100 heart attack patients, and genetically altered to make them more robust. The supercharged cells will then be injected into the patient's heart through the blocked artery. Like Keller, Stewart notes that one challenge is making sure transplanted cells stick around long enough to stimulate repair. That's where lab work comes in. "Because we're culturing our cells, they actually change shape," says Stewart, CEO and scientific director of OHRI. "They're no longer small and round; they become larger and rod-shaped. They're too big to go through capillaries directly, so they get delivered to the heart."
Stem cells don't have to come from a petri dish to have a regenerative effect: in fact, they're found throughout our bodies and help us heal "so we don't fall apart," says Dr. Marc Ruel, a cardiac surgeon at the University of Ottawa Heart Institute (UOHI). When a heart attack occurs, dying cells seem to send out signals to summon them to help fix the damaged area. Instead of transplanting cells, "the ideal may be to amplify the body's own signals and the number of cells [that respond]," says Dr. Christopher Glover, a cardiologist at the UOHI and associate professor of medicine at the University of Ottawa. He's been conducting a trial that attempts to do that.
About three years ago, Glover, 42, began recruiting 86 heart attack patients in an effort to stimulate their own cells for repair. Within five days of having a heart attack, trial participants are given a drug that pulls stem cells from the bone marrow into the bloodstream, in the hope they'll travel to the heart and become functioning heart cells. "There's some repair our bodies can do [on their own]," Glover says. "If we amplify the response, perhaps we'd get more repair." The trial is set to wrap up in the coming months; subjects are doing "even better than expected," he says.
Harnessing the body's own cells was also the goal behind an experiment that made headlines around the world in January. In what was called "the biggest heart breakthrough since the stent," Ottawa researchers created an organic, collagen-based gel that, when injected into damaged tissue, attracts the body's cells to spur regeneration. After injecting it into the thigh muscles of lab rats, which had little blood flow after the main artery was cut, the team managed to grow entirely new blood vessels over a two-week period. The gel "provides a place where the cells survive, rather than die off," explains Erik Suuronen, the UOHI scientist who led the study. Those cells then "start sending out signals to attract even more cells."
Their finding has huge implications for treating a number of conditions, including cardiovascular disease. The gel's ability to help grow muscle cells has not yet been tested, Suuronen says. But thanks to restored blood flow, "dying cells may recover," resulting in less scar tissue and a healthier organ. Of course, many challenges remain. "There's two tissues we're trying to create: blood vessels and contractile tissue," says Ruel, who collaborated with Suuronen on the project. Contractile cells have proven more difficult to recruit, he says, adding that the UOHI team is working on this puzzle now.
At Dalhousie University in Halifax, Kishore Pasumarthi, associate professor in the department of pharmacology, is aiming to reduce scar damage after a heart attack by doing what he once thought couldn't be done - kickstarting cell division in adult heart muscle tissue. Cell division in the heart stops in early infancy, he explains, which is why muscle cells that die after a heart attack are replaced by a scar. By putting cell-cycle proteins (which control cell division) into the damaged heart tissue of genetically altered mice, Pasumarthi's lab has managed to reduce scarring by 30 per cent, and to improve the heart's contractile function, too. "If we can do that, why not more?" he says. "Maybe, at one point, we won't see any scar there at all."
Cell-based therapies, many of them being developed in Canada, offer huge potential for fixing damaged hearts - although, experts say, their practical application is still a ways off. Even so, "it's not crazy to think that, in 15 years, we may treat all stable ischemic heart disease with stem cell therapy," Ruel says. Instead of mechanical interventions, like surgery or heart transplantation, he says, we're approaching "the age of biological ones."
Ruel believes it's just a matter of time. "We know it's going to work. We are living proof of it," he says. After all, each of us grew from a tiny mass of stem cells into a fully formed adult. "Nature proves this concept every day."
See also MEDICAL RESEARCH.
Maclean's March 2, 2009