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Wednesday, August 20, 2014  
Heart, heal thyself
You feel sick, dizzy and short of breath. When the pain passes, you wonder what on earth just happened. In one way you can consider yourself lucky: you have just survived a heart attack, writes Linda Geddes

It starts slowly, with a faint discomfort that grows until it feels like a vice is tightening around your chest. The pain radiates to your left arm and shoulder, and to the back of your neck. You feel sick, dizzy and short of breath. When the pain passes, you wonder what on earth just happened. In one way you can consider yourself lucky: you have just survived a heart attack.

But your troubles are far from over. When the blood supply to part of your heart was blocked, the muscle cells there died. As the dead cells are replaced by scar tissue, more and more strain will be put on the rest of the heart, causing it to enlarge and slowly fail.

This is the fate of millions of people around the world. Yet if the dead area of their hearts could be replaced with new muscle tissue, their lives would be transformed. A few years ago, doctors thought they might have the answer. They hoped that damaged hearts could be fixed by extracting stem cells from people and injecting them into the heart.

The bad news is that this approach seems to do little good. But the work has not been in vain. It has led to a series of discoveries that promise to provide better ways of regenerating the heart.

Not so long ago, few researchers entertained any hopes of regenerating the heart. While some fish and amphibians can grow new muscle if their hearts are damaged, mammals cannot. Break a human heart, and its cells will stubbornly refuse to grow back again.

But what if you could grow new cells outside the body and get them to turn into new heart muscle? This idea really took off around 2000, when it was shown that stem cells in our bone marrow have the potential to turn into heart muscle cells. If you extracted these stem cells and injected them into the heart, the thinking went, they would turn into muscle and replace any damaged tissue. “The field went through a phase of ‘have cells, will inject’,” says Rahul Aras, head of Juventas Therapeutics in Cleveland, Ohio.

While some early animal trials produced dramatic results, the results of human trials so far have been disappointing. Any improvements in heart function are usually slight, and some people developed an irregular heartbeat after certain types of cells were injected. Biologists certainly haven’t given up on the idea of repairing the heart with stem cells, though. Some are experimenting with different kinds, such as embryonic stem cells, for example. Others think it might not be necessary to inject any cells at all. Instead, they argue, if only we can discover the right signals, we could persuade the existing stem cells in our bodies to multiply, travel to the heart and repair it.

The hope is that the cells will work their way into the heart over days or weeks, which might be better than a massive one-off dose of stem cells. If it works, “in situ stem cell therapy” would have numerous other advantages over injecting cells. For starters, there would be no need to extract people’s bone marrow, which is a painful procedure, and no risk of the stem cells becoming infected or acquiring dangerous mutations when outside the body. It would also be much easier to scale up this approach to treat large numbers of people.

Doctors have long used drugs that stimulate the bone marrow to produce more blood stem cells. Building on this work, in 2009 Sara Rankin of Imperial College London and her colleagues showed that certain combinations of chemical factors make the bone marrow of mice release the kind of marrow stem cells that are capable of turning into muscle. The same chemical cocktail also releases endothelial progenitor cells, which help form new blood vessels and so might restore blood supply to the heart (Cell Stem Cell, vol 4, p 62). “We think these cells are mobilised in the context of normal injury, but we want to enhance that effect,” says Rankin.

The procedure releases a flood of stem cells into the blood within hours. It remains to be seen, however, whether this will significantly boost healing in people. Some reckon what really matters is getting stem cells to go where they are needed.

Marrow stem cells are known to bind to a protein called SDF-1, found on the surface of some other cells. So several companies, including Juventas Therapeutics, hope that getting cells in areas of tissue damage to produce SDF-1 will make stem cells remain in the area and repair the damage. “Mobilised stem cells don’t know where to go,” says Aras. “We’re creating a beacon or a signal as to where the damage has occurred, so those circulating cells move to that target.”

In a phase 1 trial, pieces of DNA containing the gene for the SDF-1 were injected into the hearts of 17 people with heart failure, resulting in the temporary production of SDF-1 in some heart cells. Last year, the company announced that the treatment appeared safe and had positive results, though this will of course have to be confirmed by larger studies.

In theory, the best results would come from combining these two approaches: getting the bone marrow to release more stem cells and getting more to stay in the heart where they are needed. But there is a twist in this tale. The whole idea behind this approach - that marrow-derived stem cells will form new heart muscle - now appears mistaken. “The heart is a complex and highly organised tissue,” says Brock Reeve of the Harvard Stem Cell Institute (and brother of actor Christopher Reeve). “Even though people could create heart muscle cells in vitro, [stem cells] don’t organise into heart tissue that can beat at a certain rate when injected into the body.”

Nevertheless, they do often seem to help. “A lot of work has now shown that these stem cells can promote the repair of heart tissue following heart attack, but without becoming part of that tissue,” says Rankin.

Sometimes a heart is so badly damaged that replacement is the only option. Instead of having to wait for scarce transplants, one day it may be possible to grow new hearts from scratch.

We have already taken big steps towards growing organs from scratch. People have been implanted with bladders, larynxes and tracheae made by seeding a scaffold with their own cells. But these are thin and relatively simple organs; the heart is a much greater challenge.

One approach to recreating its 3D structure is to grow sheets of beating heart cells in a dish, and stack them on top of one another to form thick “patches”. The individual sheets synchronise their contractions. When these patches are implanted into injured rat hearts, they even couple with the existing heart cells (Cardiology Research and Practice, vol 2011, ID 845170).

Another approach is to take hearts from people who have died, or animals, remove all the cells to leave just a framework made of collagen and then seed this scaffold with the cells of the individual who needs a new heart. At the University of Minnesota, Doris Taylor has seeded rat heart scaffolds with stem cells from newborn rats. When hooked up to a blood supply, these lab-grown hearts beat just as if they were inside a live animal’s body. These hearts are not yet strong and muscular enough to replace a rat’s normal heart, though.

Tribune Media Service
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