Step to using patient's skin cells to repair heart

Technion-Rambam scientists take first step that could eventually be used to repair damaged heart muscle.

By JUDY SIEGEL-ITZKOVICH
Prof. Lior Gepstein of Rambam Medical Center 370 (photo credit: Courtesy)
Prof. Lior Gepstein of Rambam Medical Center 370
(photo credit: Courtesy)
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 heart tissue.
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.
Prof. Lior 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.
“The 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 damage.”
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 nucleus.
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.”
The 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.