Biomedicine

Creating a Heart

An ingenious method for making new organs could one day revolutionize medical transplants.

In Doris Taylor’s cell- and molecular-­biology lab at the University of ­Minnesota, a small pink heart beats in a glass chamber amid a complex of tubes. With each twitch, the heart’s bottom tip traces a small curve in space, and pink nutrient solution flows out through the aorta. Remarkably, this living heart was grown in the lab.

Growing hearts: Doris Taylor (above) and her colleague Stefan Kren are creating live bioartificial hearts.

Taylor directs the university’s ­Center for Cardiovascular Repair, where her team has created bio­artificial hearts using a novel approach in which animal hearts act as scaffolds. The researchers begin with a rat or pig heart and chemically wash away its cells. What remains is the extracellular matrix, a complex of carbohydrates and proteins that preserves the intricate structure of chambers, valves, and blood vessels. The researchers add heart cells harvested from a newborn animal and incubate the organ in a bioreactor, which provides physio­logical cues like pressure and electrical stimu­lation. Soon, the heart begins to beat weakly on its own.

The goal is to create hearts and other organs for transplant that use the extracellular matrix of a cadaver’s or pig’s organ and are populated with a recipient’s cardiac progenitor cells. Since the re-created organ would essentially be made from the patient’s own cells, it would be compatible with his or her body. In theory, patients would not need harsh immunosuppressant drugs, because the bioartificial hearts would not provoke a strong immune response. “Even though heart transplants are great, you’re basically trading one disease for another,” says ­Taylor: immunosuppressants can cause high blood pressure and kidney disease. “Our hope is to overcome that.”

The idea of growing new heart tissue to repair heart damage is not new. Numerous groups are working on cell therapies, in which new cells are injected into a specific region of a failing heart to help restore function. In fact, Taylor herself helped pioneer that approach in earlier work at Duke University. Researchers are also developing patches of cardiac tissue that could be sewn to the surface of a sick heart to help it contract more strongly. But both approaches would primarily benefit patients whose heart damage is not very severe, ­Taylor says. By contrast, Taylor’s bioartificial hearts are aimed at patients who need organ transplants to live.

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Taylor chose to use real hearts as a starting material because the organ’s structure is too complex to build from scratch, at least in the near term. “Nature’s already figured out a way to make this scaffold,” she says, “so why try to build it when we don’t know everything that’s there?”

Gordana Vunjak-Novakovic, a ­professor of biomedical engineering at Columbia University, says that to her knowledge, this is the first time someone has “taken a whole heart and developed a system for stripping it fully of cells” in order to create a new, recellu­larized organ. “It’s very significant work,” she adds, though it “still has a long way to go” before it could be useful to patients.

Coming Alive
To flush the animal heart of cellular material, “we start with a nasty detergent that literally bursts the cells,” Taylor says. In the case of larger animal hearts, like those of pigs, a member of the center, Stefan Kren, fills a large receptacle with the detergent and lets it flow into the heart through a long rubber tube. To “decellularize” smaller organs, like rat hearts, Kren uses a piece of enclosed glassware. After cells are removed, the heart appears white and rubbery. ­Taylor points to a glass jar containing a decellularized pig heart in formaldehyde, noting that the location of the coronary blood vessels is visible. Valves are intact, she says, as are heart chambers.

The bigger challenge is adding new cells to the heart scaffolding and culturing it within the bioreactor. To prepare for this process, Kren places a decellularized rat heart in saline solution and attaches tiny catheters to the left ventricle and aorta. These are for inflow and outflow of nutrient solution, respectively. Then he hangs the organ by the aorta within the bioreactor’s central glass chamber, which is surrounded by a system of tubing. He also attaches two electrodes to the heart, one near its bottom and another near the aorta. These will help pace the heart and encourage the new cells to contract in a coördinated fashion.

The next step is particularly tricky: it involves injecting new cells, isolated from newborn rats, through the walls of the left ventricle. (For human hearts, of course, a different cell source, such as cardiac stem cells, would be needed.) “If we put too few in, they won’t interact with each other properly,” says Taylor. “If we put too many in, they’re not going to get enough oxygen and nutrients and are going to die.”

So far, her team has used a primary culture that includes four types of heart cells from neonatal rats: cardiac myocytes, endothelial cells, smooth muscle cells, and fibroblasts. The researchers have repopulated the left ventricle but have yet to complete the process with other heart chambers. Once the cells are in place, Kren begins the electrical pacing. “We usually wait a day while the cells are settling down,” he says.

At this stage, the bioreactor mimics several features of a heart-lung system. A gas mixture that is 95 percent oxygen bubbles from a steel tank into a cylinder of nutrient solution. A small pump sends that solution over to the heart, down through the catheter, and into the left ventricle. Not only does the solution provide nutrients, says Taylor, but the pumping action stretches the heart mechanically, the way a heartbeat would. “We want to train the cells so they beat in a way that gets the blood out and don’t just sit there and throb,” she says.

Starting Point
The heart in front of Taylor has been in the bioreactor for 10 days. How well would it beat on its own, when only one of its ventricles has been repopulated with cells? Kren switches off the current, and the heart’s motion decreases noticeably. Still, a rhythmic twitch is apparent in the left ventricle, indicating that cells there are beating in sync, and that the heart has started to gain some function.

The group has maintained rat hearts in the bioreactor for up to 40 days. In results published in Nature Medicine, they reported that after eight days, the hearts were able to generate roughly 2 percent as much force as an adult rat’s organ. The researchers hope to improve on this number, in part by adding cells to the scaffold more effectively.

But the next goal is truly daunting: to successfully transplant the hearts into animals. To date, the scientists have implanted hearts in the abdomens of rats for up to seven days. “We needed to show that we could sew them in and that they wouldn’t leak,” says ­Taylor. Now, however, the scientists must try to make the re-created organs take the place of the animals’ own hearts.

When it comes to making substitute hearts for people, the ­hurdles are even higher. “Where do we start?” asks Taylor. One of the greatest challenges is finding a suitable source of cells that will repopulate the heart scaffolding. Adult heart muscle cells do not divide readily. And cardiac­-derived progenitor cells, which are akin to cardiac stem cells, are not plentiful, although Taylor says her group has had some success isolating them and growing them in the laboratory. A human heart contains trillions of cells, she says. “We don’t believe we’re going to put every cell back. We believe we’re going to put some cells back and let them divide and figure out where they need to be themselves.”

If it works–and it will probably be years before that is known–the approach could transform the field of organ transplantation. “One of the best things about this process is that we’re harnessing natural processes to make things happen as they do in life,” says Kren. “We don’t have to do the heavy lifting. Nature will do it for us.”

Amanda Schaffer is a science and medical columnist for Slate and a frequent contributor to the New York Times.

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