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A rat heart in three stages of decellularization via a process developed by University professor Doris Taylor and her colleagues. See the larger image for details.
Researchers create a new heart in the lab
Work opens a new path to replacement of hearts and other organs
By Deane Morrison
In a medical first, University researchers have created a beating heart in the laboratory. Using detergents, they stripped away the cells from rat hearts until only the nonliving matrix, or "skeleton," was left; they then repopulated the matrix with fresh heart cells. If perfected, the technique may be used someday to generate new hearts for patients. In the United States alone, about 5 million people live with heart failure, 550,000 new cases are diagnosed every year, and 50,000 die waiting for a donor heart.
"The results were a home run," says Doris Taylor, director of the University's Center for Cardiovascular Repair and a principal investigator on the study. "We knew that cell therapy--that is, transplanting cells into [a patient's damaged] heart--is not a panacea. So we started thinking, 'Is there a way to use cells to engineer heart tissue?'" The idea, she says, is to create whole new blood vessels or organs by implanting a patient's own cells into a matrix derived from a donor organ. This approach ought to bypass the problem of organ rejection because the matrix, being devoid of cells, shouldn't provoke an immune response. Even if it did, the new cells would create a fresh matrix of their own, which would turn off the immune response and free patients from the need to take immunosuppressive drugs. The process, called whole organ recellularization, can be done "with virtually any organ," Taylor says.
A simple planThe main hurdle in creating new hearts wasn't finding the right cells but recreating the vastly complex architecture of the heart, Taylor explains. In puzzling it over, she and Harald Ott, a research associate in the center (now a surgical resident at Harvard Medical School and first author of the study), hit on a way to get nature to solve the problem for them. To remove cells from fresh rat hearts, the researchers pumped solutions of detergents through the network of blood vessels that normally nourish the organ. The treatment popped all the cells like balloons and washed away the debris, leaving the matrix of protein fibers that form the backbone of a living heart's connective tissue. It's called the extracellular matrix, or ECM.
"We just took nature's own building blocks to build a new organ," says Ott. Still, "When we saw the first contractions we were speechless."The naked ECMs looked strikingly like "ghost hearts": eerily white, rubbery "skeletons" that retained the organ's original 3-D structure. Among the surviving features was the tubing of blood vessels, which came in handy later.Next, the team removed hearts from newborn rats and minced them, liberating a motley crew of adult and undifferentiated cells. The mix contained stem cells and progenitor cells--which have less potential than stem cells but can still become multiple cell types--along with adult heart muscle cells and many other types. "Newborn tissue is rich in cells that are more hearty and more tolerant [than adult cells]," says Taylor. The researchers then injected these cells into the left ventricles of the ECM hearts and began pumping a solution of oxygen and nutrients through the remnant blood vessels. After four days, they detected contractions in several hearts. In eight days, they had eight hearts beating normally enough to pump fluid out the aorta. "We just took nature's own building blocks to build a new organ," says Ott. Still, "When we saw the first contractions we were speechless." As the new hearts developed, the team coaxed them along by stimulating them with electrodes. The electrical signals propagated through the tissue and synchronized the beats. When stimulation was stopped, the hearts continued beating for various periods of time on their own. The best-performing hearts were kept beating for 40 days. "We don't know yet, but the heart seems to get stronger over time as we pace it [with electrical stimulation] and increase the delivery of cells," says Taylor. "We're confident we can mimic the real heart."
A variety of
The work by Taylor, Ott, and their colleagues is part of a general movement to find better ways of fixing sick or injured hearts.
For example, the human heart normally contains stem cells that ought to be able to replace muscle damaged by heart attack or other injury. Why they don't "is the $64,000 question," according to Taylor.
"Virtually every organ has stem cells," she says. "We think that with aging and chronic disease, the number and function of stem cells decreases." Another problem is that if injured, the heart can't wait for repair. And even if the damage isn't fatal, the immune system clears away dead heart muscle and scar tissue replaces it; therefore, either the dead cells or the scar gets in the way of new muscle that might otherwise form.