Stem Cells Yield Promising Results

March 31, 2001 - The basis of a possible revolution in treating heart
attack patients
has been laid by three reports of using stem cells from bone marrow to
repair heart tissue in animals.

In one of the studies, apparently functional heart tissue was
regenerated from the injected cells, the first such success in some two
decades
of effort. In another, the stem cells morphed into new blood vessels
that rescued the heart cells around the damaged area from their usual
course of overgrowth and death. In the third, stem cells were used to
strengthen pig hearts.

The three groups of researchers, based at Columbia University, New York
Medical College in Valhalla, N.Y., the National Institutes of
Health, and Osiris Therapeutics of Baltimore, said they were a year or
more away from testing their animal techniques in people. Still,
heart disease experts believe the stem cell work is highly promising.

"The health care industry would be revolutionized if the treatment of
heart failure could be moved from organ transplants down to cell
transplants," said Dr. Mark Sussman, a heart researcher at the
Children's Hospital and Research Foundation in Cincinnati.

The new research opened "some very exciting doors," Dr. Sussman said,
but required considerable further work to make sure it was as
promising as it seemed.

Dr. Eugene Braunwald of Harvard, who is the author of a leading textbook
of cardiology, said the idea of putting stem cells into the heart
to grow new heart muscle cells was "a very interesting approach."

If their animal techniques work the same way in people, the researchers
say, people suffering a heart attack would be treated by having
cells extracted from their bone marrow. The cells would be sorted and
amplified, then injected either directly into the heart, or maybe just
into the bloodstream, from which they would home in on damaged heart
tissue and on the enlarged heart muscle cells that soon grow
around it.

It may even prove possible, though this concept has not yet been tested,
to do no more than inject a heart attack patient with a cytokine, a
natural protein that stimulates the bone marrow's stem cells to
proliferate. The cells would home in on damaged heart tissue, and repair
it.
Biologists say it is too early to know if the blood-forming stem cells
of the bone marrow are also the heart's own stem cells, which
researchers have been seeking in vain for years, or if their remarkable
ability to repair the heart is just a general property of stem cells.

Stem cells are unspecialized cells that can turn into the mature cells
of the body while replenishing their own numbers so as to remain a
constant source of new cells. The cells involved in the new reports are
called adult stem cells, and differ from the controversial embryonic
stem cells that generate the fetus and adult organism.

The new results all depend on the recent finding that the stem cells of
the bone marrow are far more versatile than supposed and can
generate other tissues besides the red and white blood cells, their
best-known function. It seems that the cells are a kind of universal
clay,
so responsive to local cues that if placed in the heart they will
develop into heart tissue instead of blood cells.

In one of the new reports, published in this month's Nature Medicine,
Dr. Silviu Itescu and colleagues at Columbia University say they
isolated a special kind of stem cell from human bone marrow. The cells,
which they call angioblasts, are a subset of the blood-forming
stem cells that make the red and white blood cells. Angioblasts generate
the cells of the fine blood vessels. Although their existence had
been inferred, they had not been isolated before, Dr. Itescu said.

After a heart attack, caused by blockage of one of the heart's own
arteries, the muscle cells that were deprived of oxygen die off and the
cells around them grow four or five times larger to compensate for the
damaged tissue. That is why most people survive a heart attack.
But the overgrown cells themselves start to die after a time, and are
replaced by scar tissue. The heart then starts to fail.

Dr. Itescu said that his team thought the overgrown muscle cells might
be dying for lack of an adequate blood supply, a point that could be
proved if the cells could be rescued with a new blood supply. This was
their rationale for learning how to isolate the angioblast cells.

They then injected human angio- blasts into rats in which heart attacks
had been induced by tying off a coronary artery. For reasons not
yet understood, stem cells are much better tolerated by the immune
system than other foreign cells. Injected into the rats' bloodstream,
the
human angioblasts homed in on the damaged heart tissue. Dr. Itescu said
he had identified the signaling chemical emitted by the damaged
heart cells, but declined to name it because he has not yet published
his description of the work.

The human angioblasts generated blood vessels within the damaged rat
hearts and prevented the overgrown heart muscle cells from dying.
The left ventricle's efficiency plunges after a heart attack, but in the
treated rats it recovered by 30 percent 15 weeks after treatment, in
step with the growth of new blood vessels.

Dr. Itescu said he hoped that clinical trials would begin in about a
year, after he had done more rat experiments to define the safety and
timing of a treatment protocol.

In a commentary, Dr. Nadia Rosenthal, a heart researcher at
Massachusetts General Hospital, called the Itescu team's success at
growing
new blood vessels a "remarkable accomplishment."

The second stem cell article, to be published in next week's Nature, was
written by Dr. Piero Anversa of the New York Medical College
in Valhalla and Dr. Donald Orlic of the National Institutes of Health
and their colleagues. The Orlic-Anversa team purified cells from a
donor mouse's bone marrow so as to isolate the most primitive stem cells
and exclude those that had already taken the first steps toward
becoming blood cells. The primitive stem cells were then injected
directly into the hearts of other mice that had been given heart attacks
by
tying off an artery.

The researchers found that the stem cells generated new heart tissue by
maturing into different cells, including heart muscle cells, the
smooth muscle cells of artery walls, and the cells that line the blood
vessel walls. The mice's left ventricle efficiency was about 40 percent
greater than that of untreated mice. This is the first time, Dr. Orlic
said, that new heart tissue has been generated from injected cells. He
and Dr. Anversa had expected to see just a few new heart muscle cells,
and had gone to great trouble to label the donor cells with a
fluorescent green protein so as to be able to tell them apart from the
recipient's heart cells.

"We never dreamed the cells could do this," Dr. Orlic said of the new
heart tissue.

Dr. Ronald McKay, an expert on neural stem cells at the National
Institutes of Health and a coauthor of the Orlic-Anversa study, was also
surprised by the new tissue formation.

"No one has ever seen this kind of thing before — complete regeneration
right across the graft site," Dr. McKay said.

Dr. Orlic and Dr. Anversa believe the new tissue is functional because
the mouse hearts improved and the new cells produced a special
protein typical of heart cells that have formed a connective network so
as to beat in unison. Dr. Sussman said this was good but not
conclusive evidence that the stem cells can make working heart tissue.

Still, Dr. Sussman wrote in a commentary in Nature, "The implications
are profound: damage to the heart muscle after a heart attack might
be reparable with specific bone marrow cells."

In a third experiment, described this month at a meeting at the Cold
Spring Harbor Laboratory on Long Island, Dr. Robert Deans of
Osiris Therapeutics said he had improved heart function in pigs by
injecting stem cells into the region of a heart attack. The pig is large
enough that the improvement in its heart function can be measured more
precisely than in rodents.

Dr. Deans used a second kind of stem cell found in the bone narrow,
known as a mesenchymal stem cell. The cells usually mature into
bone, cartilage and fat cells. Injected into the pigs' hearts, they
developed into heart muscle cells. Dr. Deans said he hoped to begin a
clinical trial of the technique in a year, probably on patients awaiting
heart transplants so that the effect of implanted cells could be
precisely measured after the old heart was removed.

Researchers have been trying for years to repair hearts by injecting
different kinds of cells into them. Their persistent lack of success,
Dr.
Sussman said, may make others wary of the new claims at first. But the
present options for treating heart failure are not so perfect: drugs
to keep the heart limping along for some years and a transplant when it
finally fails.

"So it would be beautiful and also a phenomenal saving in economic terms
and for people's quality of life if you could figure out a way to
repair the existing heart," Dr. Sussman said. "I think this therapeutic
approach, if it becomes viable, gives us an entirely new way of treating
heart failure that did not exist before."

By NICHOLAS WADE
Copyright 2001 The New York Times Company
http://www.nytimes.com/2001/03/31/health/31CELL.html?pagewanted=print

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