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The Technion researchers for the first time turned patients' skin cells into heart muscle cells in order to repair a damaged heart

However, the researchers warn that there remain a large number of hurdles that must be overcome before it will be possible to examine the use of transplanting these cells as a possible treatment for heart patients and the aforementioned process will require at least five to ten years before possible clinical trials can begin.

Prof. Lior Gepstein, courtesy of Rambam spokespersons
Prof. Lior Gepstein, courtesy of Rambam spokespersons

Technion and Rambam Medical Center researchers succeeded for the first time in taking skin cells from heart patients and reprogramming them into new, healthy heart muscle cells, which are able to integrate into existing heart tissue. This is what the scientific journal European Heart Journal publishes today. According to its editor, Professor Thomas Lisher, the breakthrough opens up a future option for treating heart patients using hiPSCs - induced pluripotent human stem cells [cells with the potential to differentiate into any cell in the body].

The researchers, Professor Lior Gapstein and PhD student Limor Zvi-Dantasis from the Rapaport Faculty of Medicine and their colleagues, say that since the reprogrammed cells originate from the patient himself, they will be prevented from being rejected by the immune system, which in other cases treats transplanted cells as a 'foreign agent'. However, the researchers warn that there remain a large number of hurdles that must be overcome before it will be possible to examine the use of transplanting these cells as a possible treatment for heart patients and the aforementioned process will require at least five to ten years before possible clinical trials can begin.

Developments in recent years in stem cell biology and tissue engineering allow researchers to consider ways to preserve and repair heart muscle using new cells, but one of the main problems is the lack of sources for producing human heart muscle cells, as well as the problem of rejection by the immune system. Research from recent years has shown that mature cells can be reprogrammed in the laboratory to create induced stem cells and these stem cells may differentiate into heart cells. However, it has not yet been proven that inducible stem cells can be created in a similar way from adult patients with advanced heart disease.

"What is new in our research is that we have shown that it is possible to take skin cells from adult patients suffering from advanced heart failure, and turn them into beating, healthy and young heart cells, belonging to the patient himself, in a laboratory dish," stressed Professor Gepstein. "These cells are the equivalent of the state of his heart cells when he was born."

The researchers took skin cells from two men suffering from heart failure, and programmed the cells by inserting three genes or "transcription factors." This programming cocktail, it is important to note, did not include the transcription factor known as c-Myc, which was previously used to create stem cells but is known to be a cancer-causing gene.

"One of the obstacles in the clinical use of hiPSCs in humans is the danger that the development of the cells will get out of control and they will turn into a tumor," explains Professor Gepstein. "This danger stems from several factors, including the oncogenic factor c-Myc, and the random integration into the DNA of the virus used to transfer the transcription factors - a process known as 'insertional oncogenesis'."

The researchers also used an alternative strategy, involving a virus that delivers reprogramming information into the cell's nucleus, but can be removed later to prevent insertional oncogenesis.

During the study, the researchers caused the patients' induced stem cells to differentiate to form beating heart tissue in the laboratory. Characterization of the resulting heart cells showed that these cells do not differ significantly in their properties from cells obtained by a similar teacher from healthy, young subjects.

Next, the researchers examined the ability of the created heart tissue to integrate into existing heart tissue. To this end, the researchers grew the resulting heart cells together with existing heart tissue. Within 24-48 hours, the tissues pulsed together. "The tissue behaved like microscopic heart tissue, made of thousands of cells in each beat zone," said Professor Gepstein.

Finally, the new tissue was transplanted into the hearts of healthy rats, and the researchers found that the transplanted tissue began to form connections with the cells of the host tissue.

"In this study, we showed for the first time that it is possible to create hiPSCs from tissues of heart patients - which represent the target audience for future cellular therapy strategies using these cells - and 'convince' them to differentiate into heart muscle cells capable of integrating into 'host' heart tissue," said Professor Gepstein. "We hope that heart cells derived from human induced stem cells will not be rejected following their transplantation in the same patients from whom they were taken. Will that happen? This question is the focus of many studies in the world. One of the obstacles in research on this topic, at the current stage, is that we can only transplant human cells into animals, so we have to inject animals with drugs that suppress the immune system so that their bodies do not reject the cells."

To translate these results into clinical treatment for heart patients, much more research is needed. "There are a large number of obstacles on the way to clinical translation," said Professor Gepstein, "among them: a quantitative increase in the number of cells, to an amount that would be clinically relevant; Development of transplantation strategies that will increase the potential of the transplanted cells to survive, develop, integrate and regenerate; Developing safe procedures that will eliminate the risks of developing cancer or problems with heart rhythm; the continuation of animal testing; and extensive industrial financing, since this is a very expensive venture. I guess it will take at least five to ten years until clinical trials, if we can overcome the mentioned difficulties."

Professor Gepstein and his colleagues will continue to investigate some of these areas, including evaluating the use of induced stem cells for cellular healing and tissue engineering to repair damaged hearts in animal models of heart failure, investigating inherited heart disorders, and developing and testing drugs.

The editor of the European Heart Journal, Professor Thomas Lischer, who is Professor and Chairman of the University Hospital Zurich and Director of Cardiovascular Research at the Institute of Physiology at the University of Zurich, Switzerland, said that "the journal is proud to publish this exciting study, which opens the door to a new approach in regenerative medicine .”

Professor Lior Gepstein is a professor of medicine (cardiology) and physiology at the Sonis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine at the Rappaport Faculty of Medicine at the Technion and the Rambam Medical Center.

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