Human heart. Credit: Bryan Brandenburg
Human heart. Credit: Bryan Brandenburg

Will we ever be able to heal damaged hearts?

Here’s the 18th piece from my BBC column

The problem with broken hearts is that they just keep breaking. While organs like your liver or skin excel at regenerating themselves after injuries, the heart is the class dunce. If its muscle cells, or cardiomyocytes, die during a heart attack, they are replaced by scar tissue rather than fresh muscle. This temporarily supports the damaged tissue but in the long term, it weakens the heart and increases the risk of more heart attacks. It’s no wonder that heart disease is the leading cause of death worldwide. By 2030, it’s estimated that failing hearts will kill more than 23 million people every year.

For now, the only way to stop the downward spiral of a damaged heart is to replace it. But donor hearts are so rare that only a few thousand transplants are carried out every year, and the lucky recipients still face a reduced life expectancy full of toxic drugs that suppress their immune systems.

Since the early 2000s, scientists have been trying to use stem cells from a person’s own body to persuade their hearts to grow new muscle. Stem cells can produce all of the various types of cell in the body, and the hope was that they’d generate new cardiomyocytes if injected into an ailing heart.

That optimism was fuelled by a study published in Naturepublished in Nature in 2001, which showed that stem cells from the bone marrow of mice could efficiently produce new muscle when injected into the rodents’ damaged hearts. Those results were refuted three years later but, by then, many clinical trials were already underway. Dozens have since been done, using stem cells taken mostly from bone marrow, but also skeletal muscles and other sources.

In 2012, the Cochrane Collaboration – an organisation that specialises in assessing medical evidence – analysed the outcomes of 33 of these trials that, between them, included 1,765 patients. Their results were underwhelming. On average, injected stem cells improved the heart’s pumping ability by just 3-4%, and they didn’t prevent further heart attacks, produce new blood vessels, or actually save lives.

That said, it’s a big ask for these cells to do what we expect. Once inside a patient, they have to survive, home in to the right parts of the heart, and produce new muscle that beats in time with existing cells. There’s little evidence that they do any of that. Even if you inject millions of cells, the vast majority of them die and disappear within a few weeks. If they have any beneficial effect, it’s probably because they send signals to existing cells that encourage them to carry out their own repairs.

These treatments might improve if, say, the cells are injected as soon as possible after a heart attack. But Paul Riley from Oxford University says “We probably parked the cart before the horse.” Driven by the dire need for better treatments for heart disease, “the field ended up pushing clinical trials more rapidly than it ought to have done,” he says.

Stem cells from bone marrow may not work, but there are more promising sources. Unexpectedly, the heart itself is one of them. Recent studies have overturned the popular idea that the adult heart doesn’t make new cells. Instead, it has its own population of stem cells that replace between 0.5-1% of cardiomyocytes every year. Perhaps the heart contains the secrets to its own salvation after all.

In the ongoing SCIPIO trial, Roberto Bolli from the University of Louisville tried using cardiac stem cells to treat 20 patients with advanced heart problems. It’s a small study, but the early results are hitting the right notes: dramatic and long-lasting improvement in pumping ability, and better quality of life.

Meanwhile, Eduardo Marban from the Cedars-Sinai Heart Institute is doing something different. He takes muscle from a healthy part of a patient’s heart, grows it in the lab to create balls of cells called cardiospheres, and then injects them back in. In a small preliminary trial called CADUCEUS, 17 patients who were injected with these clumps developed more muscle and less scar tissue, although their hearts did not pump any better.

Regeneration game

With results like these, Joshua Hare from the University of Miami says it would be wrong to dismiss cell therapy altogether. “We feel that it’s working to make patients better,” he says. It’s also safe. Barring a few earlier missteps, we now have a lot of experience of injecting cells into hearts. If someone finds a way to make the technique work, it won’t take long to hit the clinical prime-time.

Other scientists are less optimistic, and are going down an entirely different approach. Rather than injecting lab-grown cells back into the heart, they’re nudging the cells that are already there into creating new muscle. Riley, for example, exploits the fact that embryos produce legions of cardiomyocytes from the epicardium – the outer layer of the cell. This ability disappears when we’re born, but Riley managed to restore it with a protein called thymosin beta 4. When he injected it into mouse hearts, the epicardium re-awakened. When the rodents experienced heart attacks, they produced new muscle that integrated well with the existing tissues.

Last year, Deepak Srivastava from the Gladstone Institutes in San Francisco, USA achieved an even more impressive trick, and one that many thought was impossible. He transformed the fibroblast cells that make up scar tissue directly into heart muscle. All it took was three genes that control the development of the embryonic heart – Gata4, Mef2c and Tbx5 (or GMT for short). “They’re part of nature’s own toolkit for making heart cells. We just redeployed them in adults,” he says. In 2010, Srivastava used his reprogramming cocktail to change fibroblasts into cardiomyocytes in a dish. Two years later, he pulled off the same trick in living mice and with even better results. It seems that something about the heart’s natural environment makes it easier to reprogram scar tissue into coordinated, beating muscle.

This is big news. The technique avoids all the problems and uncertainties of injecting stem cells since it works with what’s already in the heart. And as fibroblasts make up half of even healthy hearts, they represent a huge reservoir of potential cardiomyocytes-to-be. “Turning scar-forming cells into muscle itself at the region of injury is very attractive,” says Riley. “That’s the cutting edge of where we’re at.”

Other scientists have since managed to reproduce these results, which comes as a relief for a field beset by contradictions and disappointments. “More and more people are using this approach and refining it,” says Srivisatava. His team is now testing the technique on pigs in a small pre-clinical trial. While mouse hearts are thin and tiny, pig hearts are a closer match for ours, and will reveal if the Srivastava’s reprogramming trick works at a human scale.

He also wants to ensure that it’s safe before moving to human trials. When working with larger hearts, the big worry is that you might create isolated pockets of reprogrammed muscle that aren’t connected to their neighbours. These could mess up the rhythm of the entire organ. Srivastava also used viruses to smuggle the GMT genes into fibroblasts.

That’s a standard part of gene therapy but it raises some red flags. There’s a risk that the viruses might insert their payload into parts of our DNA that disrupt other important genes, possibly increasing the risk of cancer. Eventually, Srivastava hopes to dispense with the GMT trinity altogether, replacing them with drugs that do the same thing. “It’d be safer and face fewer regulatory hurdles,” he says.

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