BioEd Online

Time might heal metaphorical heartbreak, but an injured heart can rarely repair itself. However, a study published today in Nature¹ reports that a natural protein can activate stem cells in mouse hearts to replace damaged tissue with new muscle cells.

Heart muscle cells, or cardiomyocytes, are irreparably damaged by heart attack. For the heart to continue functioning properly, the damaged cells must be replaced. Heart progenitor cells — cells that can form the various tissues that make up the heart, such as blood vessels and muscle — do exist, but in adults are not active enough to repair damage. So Paul Riley at University College London Institute of Child Health and his colleagues have found a way to wake them up.

Riley and his team used a small protein called thymosin ß4 (Tß4), which is found in many tissues and regulates cell structure and mobility. They had already shown that Tß4 can induce heart progenitor cells to produce new blood vessels². This time, they were looking for new muscle.

Express delivery

"We studied the activity of a gene called Wt1, because we know that embryonic stem cells expressing Wt1 can become cardiomyocytes, but Wt1 is switched off in adults," says Riley. He and his team injected mice with Tß4 every day for a week, then anaesthetized the animals and stitched together one of their arteries, mimicking a heart attack. Mice survive this procedure, making it possible to study the way their hearts respond to treatment.

The researchers examined the hearts of mice at various time points after the operation. They found heart cells expressing Wt1 just two days after the injury. The cells were initially in the heart's outer layer, but by two weeks after surgery they had moved inside and clustered around the site of the injury. The cells had also changed in size and shape, and looked just like cardiomyocytes.

Riley and his team are still working out exactly how Tß4 switches stem-cell genes in the heart cells back on, but they're betting on an epigenetic effect — a chemical change to DNA that affects gene expression. They think that the injury provides a trigger for the stem cells to go ahead and divide, making healthy new muscle cells. The researchers are also trying to work out what that injury signal actually is.

Maurice van den Hoff, a cardiac biologist at the Heart Failure Research Center in Amsterdam who was not involved in the study, says that lipid or bone-marrow stem cells have been used in heart-attack patients before, but that these stem cells don't make true cardiomyocytes, so they won't work in patients long-term. "But heart stem cells are much more likely become the right cell type, and lead to lasting repair," he says.

Wear and repair

Riley thinks that Tß4, or another molecule of similar effect, might become a daily preventative treatment for people who have a family history of heart disease, much as cholesterol-lowering drugs and anti-clotting agents have done. But Deepak Srivastava, a cardiac stem-cell biologist at the Gladstone Institute of Cardiovascular Disease in San Francisco, California, who was not part of the study, says a daily treatment is best given as a pill, and proteins such as Tß4 usually have to be delivered by injection.

Instead, he sees another possibility for the treatment. His group previously showed that treating mice with Tß4 within hours of a heart attack helps muscle cells survive the injury³. Srivastava and his co-workers are now working with RegeneRx Biopharmaceuticals of Rockville, Maryland, to test Tß4 injections in humans, and the drug has already passed safety trials. The next phase of the drug trials might change in light of the new findings, which suggest that Tß4 might continue to prime stem cells to make new cells after its initial survival effect has worn off. "Maybe we will inject for longer than 3 days," Srivastava says.

Although further experiments and clinical trials are needed to show whether Tß4 works the same way in human hearts, and whether treatment is most effective before or after a heart injury, the scientists agree that self-repair is the best medicine for a broken heart.