Nearly 5 million people live with heart failure, and about 550,000 new cases are diagnosed each year in the United States. Approximately 50,000 United States patients die annually waiting for a donor heart. To help eliminate this problem, researchers from the McGowan Institute for Regenerative Medicine and other university locations throughout the nation are working towards advances in generating heart tissue in the lab.
Work in the lab often begins with organ decellularization—the process of removing all of the cells from an organ leaving only the extracellular matrix (ECM), the framework between the cells, intact. Stephen Badylak, D.V.M., Ph.D., M.D., Deputy Director, McGowan Institute, and Research Professor in the Department of Surgery, University of Pittsburgh, has reported through his work over the years that decellularized tissues and organs have been successfully used as bioscaffolds derived from xenogeneic (derived or obtained from an organism of a different species, as a tissue graft) ECM and have been used in numerous tissue engineering applications. The safety and efficacy of such scaffolds when used for the repair and reconstruction of numerous body tissues including musculoskeletal, cardiovascular, urogenital, and skin structures has been shown in both preclinical animal studies and in human clinical studies. More than 1.5 million human patients have been implanted with xenogeneic ECM scaffolds. These ECM scaffolds are typically prepared from porcine organs such as small intestine or urinary bladder, which are subjected to decellularization and terminal sterilization without significant loss of the biologic effects of the ECM. The composition of these bioscaffolds includes the structural and functional proteins that are part of native mammalian extracellular matrix. The three-dimensional organization of these molecules distinguishes ECM scaffolds from synthetic scaffold materials and is associated with constructive tissue remodeling instead of scar tissue formation.
Regenerative medicine approaches for the treatment of damaged or missing myocardial tissue include cell-based therapies, scaffold-based therapies, and/or the use of specific growth factors and cytokines. Dr. Badylak’s lab has successfully evaluated the ability of ECM derived from porcine urinary bladder to serve as an inductive scaffold for myocardial repair.
Building on the foundation of Dr. Badylak’s work, scientists from the University of Minnesota Center for Cardiovascular Repair grew functioning heart tissue by taking rat and pig hearts and reseeding them with a mixture of live cells.
After successfully removing all of the cells from both rat and pig hearts, University of Minnesota researchers, led by Doris Taylor, Ph.D., director of the Center for Cardiovascular Repair, Medtronic Bakken professor of medicine and physiology, injected them with a mixture of progenitor cells that came from neonatal or newborn rat hearts and placed the structure in a sterile setting in the lab to grow.
The results were very promising, Taylor said. Four days after seeding the decellularized heart scaffolds with the heart cells, contractions were observed. Eight days later, the hearts were pumping.
Researchers are optimistic this discovery could help increase the donor organ pool. However, it is clear that more work is required to get a fully functional heart.
Researchers hope that the decellularization process could be used to make new donor organs. Because a new heart could be filled with the recipient’s cells, researchers hypothesize it’s much less likely to be rejected by the body. And once placed in the recipient, in theory the heart would be nourished, regulated, and regenerated similar to the heart that it replaced.
“We used immature heart cells in this version, as a proof of concept. We pretty much figured heart cells in a heart matrix had to work,” Taylor said. “Going forward, our goal is to use a patient’s stem cells to build a new heart.”
Although heart repair was the first goal during research, decellularization shows promising potential to change how scientists think about engineering organs, Taylor said.
“It opens a door to this notion that you can make any organ: kidney, liver, lung, pancreas – you name it and we hope we can make it,” she said.
The Minnesota work "fits right in with other work in regenerative medicine," said Dr. Badylak.
"Stem cells will respond depending on what they see around them," Badylak said. "What they are doing is to provide a lot of favorable signals for stem cells to become heart cells. They take stem cells that want to become heart cells and encourage them to act appropriately. It sounds great."
The newly reported work "provides great proof of principle that you can get heart tissue to form," Badylak said. "The next step is to determine how you can use this information therapeutically. The eventual goal is to put it into a patient that needs it."
The schedule for such an attempt is not clear, Taylor said. "We are certainly several years away, but not tens of years away" from a human transplant trial, she noted.
Other tissue engineering scientists around the country said there are enormous obstacles to using the technique for people.
But they described the work as exciting and a landmark.
"The biggest hurdle is cell type," said William Wagner, Ph.D., Deputy Director of the McGowan Institute. In addition, he is Professor of Surgery, Bioengineering and Chemical Engineering at the University of Pittsburgh as well as the Director of Thrombosis Research for the Artificial Heart and Lung Program. Since Taylor is an expert in stem cell biology, "I bet she is well equipped to try that," he said.
Illustration: McGowan Institute for Regenerative Medicine.
University of Minnesota Academic Health Center News Release (01/13/08)
Atlanta Journal Constitution (01/13/08)
Star Tribune (01/13/08)
NPR, All Things Considered (with audio clip) (01/13/08)
University of Minnesota Medical School News (with video link) (01/14/08)
University of Minnesota News (01/14/08)
US News & World Report (01/14/08)
Technology Review (01/14/08)
Stephen F. Badylak bio
Abstract (Nature Medicine, published online 13 Jan 2008)