Turning Scar Tissue Into a Beating Heart

Cell biologists often seem like modern-day alchemists. Instead of turning lead or straw into gold, they're looking for ways to turn one kind of cell into another, potentially more useful, cell. Now, one research team has found a way to turn a very common heart cell into a cell missing in injured hearts.

A healthy heart is a mix of several kinds of cells, including cardiomyocytes, the muscle cells that beat, and cardiac fibroblasts, which provide structural support and help keep all the heart cells working together. When a mammalian heart is injured, for example by a heart attack, it forms scar tissue dominated by fibroblasts instead of cardiomyocytes. As a result, the heart doesn't fully recover its pumping capacity. Developmental biologist Deepak Srivastava and cardiovascular researcher Masaki Ieda of the Gladstone Institute of Cardiovascular Disease in San Francisco, California, and their colleagues wondered whether some cellular alchemy could prompt the fibroblasts to turn into cardiomyocytes.

The researchers used a technique called cellular reprogramming, which others had shown can turn one cell type into another. They inserted into mouse cardiac fibroblasts extra copies of more than a dozen genes known to play a role in heart development and watched to see whether any of the cells took on characteristics of cardiomyocytes. After several rounds of tests, the scientists identified a trio of genes that together did the trick. The team inserted extra copies of the three genes into cardiac fibroblasts growing in the lab, and after 2 weeks about 20% of them took on characteristics of cardiomyocytes, expressing typical genes for the muscle cells. After growing for a month, the reprogrammed cells began to contract, like beating heart cells, the researchers report in the 6 August issue of Cell. The reprogrammed cells look and act convincingly like bona fide cardiomyocytes, says Christine Mummery, a developmental biologist not involved with the research who studies cardiac stem cells at Leiden University Medical Center in the Netherlands.

Whether these cells could actually help repair a damaged heart remains an open question, however. Transplants of heart muscle cells created from embryonic stem cells haven't worked as hoped so far—the new cells don't seem to fully integrate into the heart tissue. Ideally, Srivastava says, researchers will find small molecules that can replace the three-gene cocktail. Such molecules could be applied directly to an injured heart and turn fibroblasts into cardiomyocytes. That might lead to more effective repair, he suggests. Mummery agrees. Reprogramming cells directly in the heart "would be potentially much more interesting" than transplantation, she says. The most important question now, she says, is whether the same alchemy will work on human heart cells.