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University of Washington (UW) researchers have succeeded in engineering
human tissue patches free of some problems that have stymied stem-cell
repair for damaged hearts.
The disk-shaped patches can be fabricated in sizes ranging from less
than a millimeter to a half-inch in diameter. Until now, engineering
tissue for heart repair has been hampered by cells dying at the
transplant core, because nutrients and oxygen reached the edges of the
patch but not the center. To make matters worse, the scaffolding
materials to position the cells often proved to be harmful.
Heart tissue patches composed only of heart muscle cells couldn't
grow big enough or survive long enough to take hold after they were
implanted in rodents, the researchers noted in their article, published
last month in the Proceedings of the National Academy of Sciences.
The researchers decided to look at the possibility of building new
tissue with supply lines for the oxygen and nutrients that living cells
The scientists testing this idea are from the UW Center for
Cardiovascular Biology and the UW Institute for Stem Cell and
Regenerative Medicine, under the guidance of senior author Dr. Charles
"Chuck" Murry, professor of pathology and bioengineering. The lead
author is Dr. Kelly R. Stevens, a UW doctoral student in bioengineering
who came up with solutions to the problems observed in previous grafts.
The study is part of a collaborative tissue engineering effort called
BEAT (Biological Engineering of Allogeneic Tissue).
Stevens and her fellow researchers added two other types of cells to
the heart muscle cell mixture. These were cells similar to those that
line the inside of blood vessels and cells 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.
"These were rudimentary blood vessel networks like those seen early in embryonic development," Murry said.
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
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.
Murry noted that these results have significance beyond their
contribution to the ongoing search for ways to treat heart attack
damage by regenerating heart tissue with stem cells.
The study findings, he 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.
Future studies will try to move heart cell regeneration closer
toward clinical usefulness, according to Murry and his research team.
They forecast that such research would include testing other sources of
human cells and developing techniques to create bigger patches for
treating larger animals through surgical transplantation or through
catheter delivered injections.
Lastly, they concluded, researchers would need to test whether
tissue patches actually improve physical functioning after implantation
in damaged hearts.
In addition to Stevens and Murry, the other researchers on this
study, entitled Physiological Function and Transplantation of
Scaffold-Free and Vascularized Human Cardiac Muscle Tissue, were Kareen
L. Kreutziger, senior fellow in pathology; Sarah K. Dupras, research
scientist in pathology; F. Steven Korte, senior fellow in
bioengineering: Michael Regnier, associate professor of bioengineering;
Veronica Muskheli, research scientist in pathology; Marilyn B. Nourse,
postdoctoral scientist, Geron Corp.; Kira Bendixen, research
technologist; and Hans Reinecke, research assistant professor of
The research was supported by grants from the National Institutes of
Health, a Bioengineering Cardiovascular Training Grant, and a Pathology
of Cardiovascular Disease Training Grant.
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