Heart patients' skin cells turned into healthy heart muscle cells
In a scientific first, researchers at the Technion-Israel Institute of Technology have succeeded in taking skin cells from heart failure patients and reprogramming them to transform into healthy, new heart muscle cells capable of integrating with existing heart tissue.
The research, published online yesterday in the, opens up the prospect of treating heart failure patients with their own, human-induced pluripotent stem cells (hiPSCs) to repair their damaged hearts. Since the reprogrammed cells would be derived from the patients themselves, the problem of the patients’ immune systems rejecting the cells as “foreign” could be avoided. The researchers caution there are obstacles to overcome before it would be possible to use hiPSCs this way in humans, and it could take at least five to ten years before clinical trials could start.
Recent advances in stem cell biology and tissue engineering have enabled researchers to consider ways of restoring and repairing damaged heart muscle with new cells, but a major problem has been the lack of good sources of human heart muscle cells and the problem of rejection by the immune system. Studies have shown it is possible to derive hiPSCs from young and healthy people, and that these hiPSCs are capable of transforming into heart cells. But it had not been shown that hiPSCs could be obtained from elderly and diseased patients. And researchers had not been able to show that heart cells created from hiPSCs could integrate with existing heart tissue.
“What is new and exciting about our research is that we have shown that it’s possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young – the equivalent to the stage of his heart cells when he was just born,” said lead researcher Professor Lior Gepstein, of the Technion Faculty of Medicine, the Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, and Rambam Medical Center.
Limor Zwi-Dantsis, a PhD student in the Technion’s Sohnis Research Laboratory, Prof. Gepstein, and their colleagues took skin cells from two male heart failure patients (aged 51 and 61) and reprogrammed them by delivering three genes or “transcription factors” (Sox2, Klf4 and Oct4), followed by a small molecule, called valproic acid, to the cell nucleus. It is important to note that 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 Prof. 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, which involved a virus that delivered reprogramming information to the cell nucleus, but which was capable of being removed afterwards so as to avoid insertional oncogenesis.
The resulting hiPSCs were able to differentiate to become heart muscle cells (cardiomyocytes) just as effectively as hiPSCs that had been developed from healthy, young volunteers who acted as controls for this study. Then the researchers were able to make the cardiomyocytes develop into heart muscle tissue, which they cultured together with pre-existing cardiac tissue. Within 24-48 hours the tissues were beating together, and the tissue was behaving like a tiny microscopic cardiac tissue comprised of approximately 1000 cells in each beating area.
When the new tissue was transplanted into healthy rat hearts, the researchers found that the grafted tissue started to establish connections with the cells in the host tissue.
“We have shown for the first time that it’s possible to establish hiPSCs from heart failure patients – who represent the target patient population for future cell therapy strategies using these cells – and to coax them to differentiate into heart muscle cells that can integrate with host cardiac tissue,” said Prof. Gepstein.
“We hope that hiPSCs derived cardiomyocytes 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. One of the obstacles in dealing with this issue is that, at this stage, we can only transplant human cells into animal models and so we have to treat the animals with immunosuppressive drugs so the cells won’t be rejected.”
Much research has to be conducted before these results could be translated into treatment for heart failure patients in the clinic. According to Prof. Gepstein, the many obstacles to clinical translation include: scaling up to derive a clinically relevant number of cells; developing transplantation strategies that will increase cell graft survival, maturation, integration and regenerative potential; developing safe procedures to eliminate the risks for causing cancer or problems with the heart’s normal rhythm; further tests in animals; and large industry funding.
The research team will now conduct 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.
(Note: this article was adapted from the official news release issued by the European Heart Journal.)