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UW researchers improve method for engineering cardiac tissue patches from stem cells
UW stem cell researcher Chuck Murry and his colleagues have been among the nation’s leaders in using regenerative medicine approaches for treating hearts damaged by disease or heart attacks. Now, they have made a major improvement in one of those methods using engineered tissue patches to implant cardiac muscle cells in a damaged area of the heart.
Murry and Kelly Stevens, a doctoral student in bioengineering, along with others from Murry’s research team, published their findings in the Proceedings of the National Academy of Sciences this fall. The researchers had hoped to improve on the results seen so far when using patches made simply of cardiac muscle tissue. In those cases, the patches died off when nutrients and oxygen reached the edges but not the center of the tissue, or harmful effects were seen from the scaffolding materials that held the patches together. Stevens worked with Murry to come up with solutions to these problems -- the researchers decided to engineer patches with built-in supply lines for nutrients and oxygen. Instead of just using cardiac muscle cells, they added two other types of cells: one type similar to those that line the inside of blood vessels, and another similar to those that provide the vessel's muscular support. All of the heart muscle cells were derived from embryonic stem cells, while the vascular cells were derived from embryonic stem cells or a variety of more mature sources such as the umbilical cord. The resulting cell mixture began forming a tissue containing tiny blood vessels, much like the ones seen early in embryonic development. In contrast to the heart muscle cell-only tissue, which failed to survive transplantation and which remained apart from the rat's heart circulatory system, the pre-formed vessels in the mixed-cell tissue joined with the rat's heart circulatory system and delivered rat blood to the transplanted graft. "The viability of the transplanted graft was remarkably improved," Murry observed. "We think the gain in viability is due to the ability for the tissue to form blood vessels." Equally as exciting, the scientists observed that the patches of engineered tissue actively contracted. Moreover, these contractions could be electronically paced, up to what would translate to 120 beats per minute. Beyond that point, the tissue patch didn't relax fully and the contractions weakened. However, the average resting adult heart pulses about 70 beats per minute. This suggests that the engineered tissue could, within limits, theoretically keep pace with typical adult heart muscle, according to the study authors. Another physical quality that made the mixed-cell tissue patches superior to heart muscle-cell patches was their mechanical stiffness, which more closely resembled human heart muscle. This was probably due to the addition of supporting cells, which created connective tissues. Passive stiffness allows the heart to fill properly with blood before it contracts. When the researchers implanted these mixed celled, pre-vascularized tissue patches into rodents, the patches grew into cell grafts that were ten times larger than the too-small results from tissue composed of heart muscle cells only. The rodents were bred without an immune system that rejects tissue transplants. The study findings, Murry observed, suggest that researchers consider including blood vessel-generating and vascular-supporting elements when designing human tissues for certain other types of regenerative therapies unrelated to heart disease. One of the major obstacles still to be overcome is the likelihood that people's immune systems would reject the stem transplant unless they take medications for the rest of their lives to suppress this reaction. Murry hopes someday that scientists would be able to create new tissues from a person's own cells. “Researchers can currently turn human skin cells back to stem cells, and then move them forward again into other types of cells, such as heart muscle and blood vessel cells,” Murry said. “We hope this will allow us to build tissues that the body will recognize as 'self.'” While the clinical application of tissues engineered from stem cells in treating hearts damaged from heart attacks or birth defects is still in the future, the researchers believe progress has been made. This study showed that researchers could create the first entirely human heart tissue patch from human embryonic cell-derived heart muscle cells, blood vessel lining cells and fiber-producing cells, and successfully engraft the tissue into an animal. |
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