Johns Hopkins scientists have successfully grown large
numbers of stem cells taken from adult pigs' healthy heart
tissue and used the cells to repair some of the tissue
damage done to those organs by lab-induced heart attacks.
Pigs' hearts closely resemble those of humans, making them
a useful model in such research.
Following up on previous studies, Johns Hopkins
cardiologists used a thin tube to extract samples of heart
tissue no bigger than a grain of rice within hours of the
animals' heart attacks, then grew large numbers of cardiac
stem cells in the lab from tissue obtained through biopsy,
and within a month implanted the cells into the pigs'
hearts. With help from a blue-dye tracking system, the
scientists have shown that within two months the cells had
developed into mature heart cells and vessel-forming
endothelial cells.
"This is a relatively simple method of stem cell
extraction that can be used in any community-based clinic,
and if further studies show the same kind of organ repair
that we see in pigs, it could be performed on an outpatient
basis," said Eduardo Marban, senior study author and
professor and chief of cardiology at the School of Medicine
and its
Heart Institute. "Starting with just a small amount of
tissue, we demonstrated that it was possible, very soon
after a heart attack, to use the healthy parts of the heart
to regenerate some of the damaged parts."
Marban cautions that no overall improvements in heart
function have yet been shown in these studies, which were
not designed to establish such changes and which used
relatively low numbers of infused cells (10 million or
less). "But we have proof of principle, and we are planning
to use larger numbers of cells implanted in different sites
of the heart to test whether we can restore function as
well," he said. "If the answer is yes, we could see the
first phase of studies in people in late 2007."
The most recent Johns Hopkins findings were presented
Nov. 13 at the American Heart Association's annual
Scientific Sessions in Chicago. They are believed to be the
first results in animal studies to show that so-called
cardiac stem cell therapy can be successfully applied with
minimally invasive methods to circumstances closely
resembling those in humans. Scientists say the results
build on earlier studies with cardiac stem cells in mice
and humans that demonstrated success in regenerating
infarcted heart muscle and restoring heart cell function
post-infarct.
For the study, cardiac stem cells were extracted by
tissue biopsy from eight pigs whose main arterial blood
supply was tightened for more than two hours, duplicating
the effects and damage caused by heart attack.
Using techniques developed in Marban's lab,
researchers extracted about a million cardiac stem cells
from undamaged heart tissue, growing them without the use
of potentially dangerous chemical stimulators.
After three weeks, the stem cells turned into
spherical balls of cells that mimicked the electrical
properties of heart muscle cells. The so-called
cardiospheres yielded on average more than 14 million
cells.
Within a month after the initial heart attack, a
catheter tube was inserted into an artery in the pig leg
for infusing the cardiospheres. Previous research had shown
that they would on their own migrate to the damaged zones
of the heart. Marban's team was able to confirm this
because they had labeled the stem cells with a gene that
codes for an enzyme producing a blue dye, which could be
seen under a microscope.
Months later, when researchers examined the hearts to
see if any damaged tissue had been repaired, they found
blue spots indicating where the stem cells had taken
root.
Closer examination of results revealed that stem cells
had matured and grown in the border zones of the damaged
area, where researchers suspect both dead and living tissue
mingle and some blood supply remains.
"The goal is to repair heart muscle weakened not only
by heart attack but by heart failure, perhaps averting the
need for heart transplants," said Peter Johnston, study
author and a Reynolds Foundation postdoctoral cardiology
research fellow at Johns Hopkins' Heart Institute. "By
using a patient's own adult stem cells rather than a
donor's, there would be no risk of triggering an immune
response that could cause rejection."
The studies were supported by the Donald W. Reynolds
Foundation. Co-authors were Tetsuo Sasano, Kevin Mills, Amr
Youssef, Mark Pittenger and Richard Lange. Marban is also
the Michel Mirowski, M.D., Professor of Medicine at Johns
Hopkins and director of its Donald W. Reynolds
Cardiovascular Clinical Research Center and the Institute
of Molecular Cardiobiology. Johnston's work on this study
was recently recognized at Johns Hopkins, on Oct. 26, with
one of three Stanley L. Blumenthal Cardiology Research
Awards.
Under a licensing agreement between Capricor and The
Johns Hopkins University, Marban is entitled to a share of
royalty received by the university on sales of products
described in this presentation. Marban and his spouse own
Capricor stock, which is subject to certain restrictions
under university policy. Marban is also a paid consultant
to Capricor. His spouse is chief executive officer of the
company and serves on the company's board of directors. The
terms of this arrangement are being managed by The Johns
Hopkins University in accordance with its
conflict-of-interest policies.
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