Prof. Lior Gepstein in his Technion laboratory – The proof of concept works, and that is an achievement.Imagine a day when doctors can repair the damaged parts of a heart which has suffered a heart attack with regenerated tissue that will contain a built-in natural pacemaker.

The prospect of using human embryonic stem cells to treat heart attacks and other diseases appears a step closer as the result of a successful Israeli experiment that showed that the versatile cells can serve as ‘biological pacemakers’, correcting faulty heart rhythms when injected into the failing hearts of pigs.

Heart disease is the leading cause of death in the U.S. Abnormally slow heart rate develops in older patients, who can only survive with an electronic pacemaker. During heart attacks, tissue is destroyed when blood is temporarily cut off to a section of the heart, and this tissue can never be repaired.

The Israeli breakthrough could result in developments that would offer relief for hundreds of thousands of people around the world who now use artificial pacemakers to regulate the beating of their heart because the normal cells that generate the rhythm work irregularly, or because they have a break in the cell system of the heart used to spread the natural pacemaking nerve signal.

The Israeli experiment centered on human embryonic stem cells, derived from donated five-day-old embryos, which have the biological potential to morph into virtually all of the 200 or so kinds of cells in the body. Researchers are racing to learn how to direct them to develop into specific types of cells that can be transplanted into failing organs.

The team from the Technion-Israel Institute of Science – headed by Prof. Lior Gepstein of the Bruce and Ruth Rappaport Institute of Medical Sciences at the Technion Faculty of Medicine and including leading stem cell researcher Prof. Joseph Itskovitz-Eldor of Rambam Medical Center’s obstetrics and gynecology department, – showed that the cardiomyocytes (heart muscle cells) created from tiny human embryos integrated functionally into the pigs’ hearts.

“This has been a long process,” Gepstein told ISRAEL21c. “Our first step was generating cell types from stem cells in the lab. We then succeeded in generating heart cells a few years ago. The next step was not only to generate but to show that these cells could function in vivo, and integrate with other networks of cells, and we have now done that.”

Rappaport Institute dean Dr. Rafael Beyar said that this was the first time that researchers anywhere had constructed beating heart tissue out of fetal stem cells, and implanted them in a pig’s heart. The team’s research, which began four years ago, opens the possibility of eventually using human embryonic stem cells to repair damaged human hearts. Ultimately, such cell therapies might be used in addition to or in place of mechanical pacemakers.

“This is extremely important research,” David Gutterman, associate director of the Cardiovascular Research Center at the Medical College of Wisconsin in Milwaukee said. “This could lead to a replacement of the mechanical pacemaker, which requires surgery to replace the battery every few years. We could also replace beating cells in patients who have had heart attacks.”

Technion scientists are widely recognized as pioneers in stem cell research. Itskovitz-Eldor was among the team that first discovered in 1998 the potential of stem cells to form any kind of tissue. Technion researchers have since grown heart tissue, blood vessels, and human insulin-secreting cells from embryonic stem cells. And scientists at the Technion are now able to grow an infinite number of cells without a feeder layer, making these cells appropriate for eventual human transplantation.

In previous experiments, the same team made news by being the first to create differentiated heart cells from human embryonic stem cells. They took cultures of functional heart cells taken from rats and added human cells: they beat together for several weeks. “But it was important not just to create such cells, but to prove that they can survive and function in the body, making functional connections with existing heart tissue cells,” Gepstein explained.

“Our current achievement shows that the cells can replace the electrical activity of the heart, and act as a kind of biological pacemaker. We’ve shown that it can survive and function and integrate with existing cells, and potentially work as a biological alternative to electrical pacemakers.”

Gepstein’s team started with masses of stem cells growing in laboratory dishes, from which they isolated those few that were spontaneously developing into heart cells. They were easy to spot: They were the ones pulsing in unison, as heart cells do.

The ultimate goal in cardiological research is to improve function after a major heart attack, wherein about a quarter of the four billion cells that make up the heart tissue die, Gepstein told The Jerusalem Post. “To do this, one needs to create enough healthy heart cells that survive the transplant and connect electrically with existing heart cells so they beat in unison. It worked in the lab, so we proceeded to pigs.”

The team threaded a probe into the hearts of the13 pigs and made a small burn in the area that regulates heartbeat, causing a permanent severe slowing of those animals’ heart rates. The injury mimicked a human heart rhythm disorder that could be caused by disease or a small heart attack.

Then they injected about 100,000 of their human embryo-derived heart cells into the pig hearts. Eleven of the 13 returned to faster heart rates, the team reported in the current edition of Nature Biotechnology.

The transplanted human cells acted like a biological version of an electronic pacemaker. In five pigs, the activity was limited to isolated beats or short runs. But in the remaining six, the hearts developed a “regular, sustained and haemodynamically stable rhythm”, the scientists reported.

The success of the experiment raises the possibility that tissue transplants could replace electronic pacemakers. Because they would be natural, the cell implants would need no power source and, over time, would integrate naturally with the heart. They could even be genetically engineered or manipulated to enhance or alter their function, say scientists.

Artificial pacemakers can bring a host of problems along with their life-saving capability. The electronic systems work by giving the heart muscle a regular electrical stimulus to make it beat. But mobile phones and other equipment can interfere with their function.

Although many obstacles need to be overcome before biological pacemaker cells can be used in practice – such as ensuring they cannot form tumors – the proof-of-principle research, carried out by a team in Israel, is a landmark.
“These results suggest the potential utility of these cells to serve as a biological pacemaker and for cardiac regenerative medicine in general,” the team wrote in their report.

The scientists said pacemaker cells could theoretically be made in unlimited numbers, and could easily be engineered to give them different functions. But a biological pacemaker from embryonic stem cells is a new concept, Gepstein said, adding that he can’t predict when it would assist or replace mechanical pacemakers.

“We have to prove a biological pacemaker will function non-stop for years in a sickly heart and wouldn’t be rejected by the recipient’s immune system. As researchers learn to create unlimited amounts of differentiated heart cells from embryonic stem cells, the technique could eventually be used to regenerate and repair hearts suffering from cardiac insufficiency. We have proven a number of important things and are the most advanced in this field. But there are still many obstacles, and we can’t say how long this will take,” Gepstein said.

“One of our next focuses is trying to improve the function of the heart after a major heart attack. We want to replace the area of the heart that dies and is now replaced by scar tissue with new cells that will be able to improve mechanical function. For the electrical repair that we’ve done, we need several thousand cells, but in contrast, for this project we need close to a billion! So we need to generate many more heart cells before this stage can become a reality.

“We also still need to find a way to combat the possibility of immune rejections. And we need to show that the cells – like an electronic pacemaker – can maintain the heart for a long period of time.”

Despite the caution, Gepstein is satisfied that the team is on the right track, each step in the process brings it one step closer to reality.

“The proof of concept works, and that is an achievement.”