New heart muscle cells grow from patients' skin

In a world first, scientists have grown new, healthy heart muscle cells using skin cells from heart failure patients. Writing about their work in a paper published online this week in the European Heart Journal, the Israel-based team explain how the new heart muscle cells are capable of integrating with exisiting heart tissue, opening up the prospect of repairing heart damage in heart failure patients using their own stem cells. However, the researchers caution there are still many hurdles to overcome before such a method is available for patients, and estimate it may take five to ten years before clinical trials can begin. The lead researcher of the study is Lior Gepstein, Professor of Medicine (Cardiology) and Physiology at the Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Technion-Israel Institute of Technology and Rambam Medical Center in Haifa, Israel. Advances in stem cell biology and tissue engineering bring ever closer the prospect of repairing damage heart muscle with new cells, but considerable challenges remain, not least how to source a good supply of new, healthy human heart cells without the immune system rejecting them. Gepstein and colleagues took skin cells from elderly heart failure patients and reprogrammed into human-induced pluripotent stem cells (hiPSCs), a type of stem cell that has the potential to become almost any type of cell in the body. They then showed that the hiPSCs could differentiate to become heart muscle cells (cardiomyocytes) that were able to integrate into heart tissue in rats. Creating heart muscle cells from hiPSCs derived from skin cells is not new, it has been done several times before, but in those cases, the skin cells came from healthy, young volunteers. As Gepstein told the press: "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." "In this study 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 coax them to differentiate into heart muscle cells that can integrate with host cardiac tissue," he added. Another obstacle that is causing headaches in this field is how to make stem cells without them developing out of control and growing into tumors. It appears that Gepstein and colleagues may have found a way around this one too. They took skin cells from two male heart failure patients (one aged 51, the other 61), and reprogrammed them by inserting three genes (the transcription factors Sox2, Klf4 and Oct4) and a small molecule, valproic acid, into the nuclei of the cells to integrate with the cellular DNA. But they did something different to what has been done before: they did not add the transcription factor c-Myc to the cocktail. This has been added in the past, but is now thought to be the cancer-causing culprit. Gepstein explained that the potential risk of the cells growing out of control and developing into tumors could also arise from 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". So, to eliminate the potential risk from insertional oncogenesis, the researchers still used a virus to deliver the reprogramming information to the cell nucleus, but then removed it afterwards. The results showed that the hiPSCs successfully differentiated into heart muscle cells or cardiomyocytes as effectively as those derived from the controls for the study, in this case healthy, young volunteers. Then, the cardiomyocytes developed into heart tissue, which the researchers cultured with pre-existing cardiac tissue. 24 to 48 hours later, they were beating together. Gepstein said they were "behaving like a tiny microscopic cardiac tissue comprised of approximately 1000 cells in each beating area". In the final step of their study, the researchers trasplanted the newly formed tissue into the hearts of healthy live rats, and showed it established connections with cells in the host heart muscle. The question of whether new heart muscle cells grown this way will be rejected by the patient still remains. "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," explained Gepstein, adding that there is still a long way to go before this kind of treatment will be available in the clinic. He listed some of the obstacles that still have to be overcome, such as: "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 since it is likely to be a very expensive endeavour." "I assume it will take at least five to ten years to clinical trials if one can overcome these problems," he added. Meanwhile the team continues to work in this area. They are planning to evaluate hiPSCs for repairing damaged hearts in various animal models, plus look into cardiac disorders, drug development and testing.