In experiments in the lab and with guinea pigs,
researchers from Johns Hopkins have found the first
evidence that genetically engineered heart cells derived
from human embryonic stem cells might one day be a
promising biological alternative to the electronic
pacemakers used by hundreds of thousands of people
worldwide.
Electronic pacemakers are used in children and adults
with certain heart conditions that interfere with a normal
heartbeat. However, these life-saving devices can't react
the way the heart's own pacemaker normally does — for
example, raising the heart rate to help us climb stairs or
react to a scary movie.
In the researchers' experiments, described in the Dec.
20 advance online edition of Circulation, human
embryonic stem, or ES, cells were genetically engineered to
make a green protein, grown in the lab and then encouraged
to become heart cells. The researchers then selected
clusters of the cells that beat on their own accord,
indicating the presence of pacemaking cells. These clusters
triggered the unified beating of heart muscle cells taken
from rats and, when implanted into the hearts of guinea
pigs, triggered regular beating of the heart itself.
"These implanted cells also responded appropriately to
drugs used to slow or speed the heart rate, which
electronic pacemakers can't do," said study leader Ronald
Li, assistant professor of
medicine. "But many challenges remain before this
technique could be used for patients. We want to bring this
to the clinic as fast as possible, but we need to be
extremely careful. If this process isn't done properly, it
could jeopardize a very promising field."
The genetic engineering of the ES cells, accomplished
by Tian Xue, a postdoctoral fellow at the
School of Medicine, inserted a gene (for green
fluorescence protein) so that the human cells would be
easily distinguished from animal cells in the experiments.
Since the engineered cells survived and worked properly,
other more clinically important genetic engineering of the
cells also will probably not interfere with the cells'
fate, the researchers said.
"To our knowledge, these are the first genetically
engineered heart cells derived from human ES cells," Xue
noted. "We're now using genetic engineering to customize
the pacing rate of these cells, for example. For any future
clinical applications, you want to make sure that the
beating rate is what you want it to be."
First isolated at the University of Wisconsin, the
human ES cells used by the researchers have the natural
ability to become any type of cell found in the human body,
and therefore they hold the potential to replace damaged
cells. But such applications await proof that the desired
type of cells can be obtained, isolated and controlled
because expected risks include primitive cells developing
into tumors or implanted cells being rejected.
In the researchers' experiments, clusters of beating
human heart cells derived from ES cells were injected into
the heart muscle of six guinea pigs. A few days later, the
researchers destroyed each animal's own pacemaking cells,
located near the point of injection, by freezing them.
Careful electrical measurements on the hearts revealed a
new beat, coordinated by the implanted human cells and
slower than the animals' normal heart rate — likely
reflecting humans' lower heart rate.
To prove that the human heart cells were controlling
the beat of the guinea pigs' hearts, colleagues Fadi Akar
and Gordon Tomaselli conducted careful experiments that
showed exactly where the electrical signal originated and
followed the signal's conduction across the heart's
surface. Sure enough, the signal started from the
transplanted human cells, easy to locate because of their
fluorescence.
"We've answered three very important questions," Xue
said. "We've shown that these human cells survived when we
put them into the animals, they were able to combine
functionally with the animal's heart muscle, and they
didn't create tumors for as long as we have watched."
But new questions have come up because of these
promising results, Li noted. For instance, the researchers
don't know why the animal's immune system didn't attack and
kill the human cellular "invaders" — that was a
surprise. One possibility is that the cluster of cells
didn't connect enough with the animal's circulatory system
to trigger an immune response, but more experiments will be
necessary to see whether that's the case and, if so, how
that might affect the implanted cells' long-term
survival.
The researchers weren't too surprised that no tumors
formed over the course of a few months of observation,
however, as they had selected beating heart cells and left
behind any cells that weren't adequately specialized.
The stem cell approach isn't the first Johns Hopkins
research to create a biological pacemaker, but it is likely
to be a better choice if the heart is very damaged. In
2002, Hopkins scientists reported that inserting a
particular gene into existing heart muscle cells in a
guinea pig allowed the cells to create a pacemaking signal.
If heart damage is extensive, however, it might be
preferable to introduce new pacemaking cells rather than to
convert existing cells into pacemakers, Li said.
The research was funded by the National Heart, Lung
and Blood Institute, the Blaustein Pain Research Center,
the Croucher Foundation and the Cardiac Arrhythmias
Research and Education Foundation. Authors are Xue, Li,
Akar, Tomaselli, Eduardo Marban, Heecheol Cho, Suk-ying
Tsang and Steven Jones, all of Johns Hopkins.
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