Scientists at the University of Minnesota have taken a big step toward making replacement organs with the recipients’ cells. In experiments performed on rats and pigs, the researchers stripped donor hearts of their cells to create scaffolds on which the recipients’ cells were grown. The hope is that a similar approach might someday prove useful to human patients with end-stage heart disease. In theory, these novel hearts could prove to be better than traditional donor hearts because they are less likely to cause an immune response.
“It’s an audacious, gutsy, exciting piece of work,” says Buddy Ratner, a professor of bioengineering and chemical engineering at the University of Washington, who was not involved in the research. Still, substantial hurdles remain before the approach might be applicable to human patients.
“This is just a first proof of concept, showing that it’s not completely crazy” to try to decellularize a whole heart and repopulate it with new cells, says Doris Taylor, director of the Center for Cardiovascular Repair at the University of Minnesota. Her team’s work was published yesterday in Nature Medicine online.
In order to create decellularized scaffolds, Taylor and her team perfused rat hearts with detergents. When the cells were removed, a complex architecture of white extracellular matrix remained. The anatomy of the heart chambers seemed to be intact, as did the valves and blood vessels, says Taylor.
The researchers reseeded the scaffolds with cardiac and endothelial cells taken from rats. Then they placed these constructs in bioreactors that simulated blood pressure, electrical stimulation, and other aspects of cardiac physiology. “We wanted to treat the cells as if they were in a heart and see if they behaved accordingly,” Taylor says. After four days, the cells in the hearts began to contract. After eight days, the hearts were able to pump with about 2 percent of the force of an adult rat heart, according to the paper.
“This is the ultimate biomimetic approach to cardiac tissue engineering,” says Gordana Vunjak-Novakovic, a professor of biomedical engineering at Columbia University. A decellularized whole heart matrix provides “practically an ideal scaffold,” she says, since it preserves much of the composition, structure, and mechanical properties of the heart.
In theory, if hearts could be made this way for human patients, they might offer an alternative to traditional donor hearts. Theoretically, patients would not need to take immunosuppressant drugs since the new constructs would be built with their own cells.
Still, the method would require a cadaver heart (or possibly a pig heart) from which to make the scaffold. It still “takes a heart to make a heart, and we can’t spare any hearts at the moment,” says Ratner.
Another challenge would be securing appropriate human cells–in sufficient quantity–to repopulate the scaffold. Adult heart-muscle cells, or cardiomyoctyes, do not proliferate, says Vunjak-Novakovic. Nor can these cells be made from readily available sources such as adult cells derived from bone marrow. Resident stem cells are a potential source, but they are not plentiful. Embryonic stem cells are also a possibility, but they need to be directed to differentiate into a desired tissue and customized in order to be accepted by patients.
Additional challenges, which might prove more difficult for larger human hearts, include loading the scaffold with the appropriate numbers of cells, keeping the cells alive with sufficient nutrients and oxygen, and having them mature properly.
Creating a heart that is electrically stable over long periods of time may also be difficult, says Richard Lee, a cardiologist at Brigham and Women’s Hospital, in Boston, and a professor at Harvard Medical School.
In addition, the heart would have to be able to exist in vivo for long periods of time without causing blood clots or strokes. “There’s a long way to go before you could actually feel like this is on the horizon” for treating patients, says Lee.
In recent years, research on cardiac tissue engineering has proliferated greatly. Many groups now use cells in conjunction with various kinds of scaffolding material to try to reconstruct either vascular or cardiac tissue structure.
While the heart envisioned by Taylor might be an alternative to transplant for some patients with end-stage heart disease or congestive heart failure, other work is aimed at repairing localized areas of damage, such as that caused by myocardial infarction, or heart attack.
For instance, several groups are currently working on cardiac patches, which are bands of engineered tissue that can be surgically applied over a damaged area of the heart in order to help restore its function.
Researchers working on cardiac patches face some of the same challenges that Taylor’s group does: securing appropriate cells, growing them on a scaffold, and successfully integrating them into the body, says Vunjak-Novakovic. Her group is engineering patches using human adult stem cells and human embryonic stem cells, with the goal of revascularizing and rebuilding cardiac structure in an area that has been damaged by a heart attack. Cardiac patches have shown some promise in animal studies but have yet to be tested in human trials.
Taylor says that her team’s decellularized heart technology might also be used to create a portion of a heart like a wall or a ventricle, or a section of tissue that could be used as a patch.
Another approach is to inject cells into damaged heart regions with the hope of rebuilding or repairing heart tissue and vasculature. Lee says that injecting bone-marrow cells into the heart’s arteries has shown some success in improving ejection fraction (the percentage of blood ejected with each beat) and other measures of heart function in human clinical trials.
Given the enormous number of patients in need of new options, Lee adds, “everything should be on the table. We can’t give up on any approach, no matter how wild or improbable, until we get better treatments to these people.”