Haifa scientists have taken a first-ever step in the use of adult human stem
cells by reprogramming skin cells from two heart failure patients and turning
them into healthy, new heart muscle cells capable of integrating with existing
Eventually the technique could be used to repair such
patients’ damaged heart muscle, but it will take between five and 10 more years
to start implementing the technique in clinical trials.
Gepstein, a senior cardiologist who has spent years on cardiac stem cell
research, headed the team from the Technion-Israel Institute of Technology and
Rambam Medical Center.
The research, published on Wednesday in the online
edition of the European Heart Journal (of the European Society of Cardiology),
opens up the prospect of treating heart failure patients with their own, human
induced pluripotent stem cells (hiPSCs) to repair their damaged hearts. Until
now, such a reprogramming process has been performed only on mice.
two patients, aged 51 and 60, both had suffered heart attacks, which caused
serious cardiac damage. We implanted automatic defibrillators to make their
heartbeats steady and keep them alive,” Gepstein told The Jerusalem Post. “At
the same time, we took a bit of skin tissue from the patients to check whether
in the future, such stem cells could be taken from patients to treat their own heart
Gepstein and his team previously performed such a technique on
the skin cells of healthy young people and those free from genetic disease that
would have weakened their hearts. “But that research did not make it clear if we
could create hiPSCs from tissue from patients suffering from heart failure” in
which the heart muscle is so damaged that it cannot properly push the blood
through the body.
“We coaxed the skin cells to differentiate into heart
cells; they showed healthy properties as if they belonged to hearts in babies.
Even though the patient’s heart cells are sick and senescent, the reprogrammed
cells are young and healthy,” Gepstein explained.
“The next stage was to
see if the heart stem cells would integrate and work in synchrony with the
patient’s older cells. We cultured them with rat cells and mapped their
electrical activity [which indicates heartbeat]. In a few hours, their
electrical activity did integrate with the older cells. We haven’t done this yet
in humans,” the Technion cardiologist said.
Within 24 to 48 hours, the
tissues were beating together.
“The tissue was behaving like a tiny
microscopic cardiac tissue comprised of approximately 1,000 cells in each
beating area,” said Gepstein.
As the reprogrammed cells would be derived
from the patients themselves, this could avoid the problem of the patients’
immune systems rejecting the cells as “foreign.”
However, it would take
up to a decade for this to be used on patients. A major problem in repairing
heart muscle has been the lack of good sources of human heart muscle cells and
the risk of rejection by the immune system.
The reprogramming was carried
out by delivering three genes or “transcription factors” (Sox2, Klf4 and Oct4),
followed by a small molecule called valproic acid, to the cell
Crucially, this reprogramming cocktail did not include a
transcription factor called c-Myc, which has been used for creating stem cells
but which is a known cancer-causing gene.
“One of the obstacles to using
hiPSCs clinically in humans is the potential for the cells to develop out of
control and become tumors,” explained Gepstein. “This potential risk may stem
from several reasons, including the oncogenic factor c-Myc, and the random
integration into the cell’s DNA of the virus that is used to carry the
transcription factors – a process known as insertional oncogenesis.”
researchers also used an alternative strategy involving a virus that delivered
reprogramming information to the cell nucleus but was capable of being removed
afterwards to avoid insertional oncogenesis.
“We hope that cardiomyocytes
derived from hiPSCs will not be rejected following transplantation into the same
patients from which they were derived. Whether this will be the case or not is
the focus of active investigation,” Gepstein said. “One of the obstacles in
dealing with this issue is that, at this stage, we can transplant human cells
only into animal models, so we have to treat the animals with immunosuppressive
drugs so the cells won’t be rejected.”
Gepstein and his team will be
carrying out further research into some of these areas, including evaluating
using hiPSCs in cell therapy and tissue engineering strategies for repairing
damaged hearts in various animal models, investigating inherited cardiac
disorders, and drug development and testing.