For the first time, researchers have successfully taken skin cells from a heart failure patient and reprogrammed them to be new heart muscle cells that can integrate into the existing heart.
The research, just published in the European Heart Journal, will make it possible to treat heart failure by using the patient’s own cells, reprogrammed into pluripotent stem cells (hiPSCs). This will avoid any potential rejection by the patient’s immune system, which sometimes occurs when someone else’s cells are used. The researchers warn though that there is a lot of work to be done, and it will take at least 5-10 years before clinical trials could begin.
It had previously been possible to repair heart failure with new cells, but heart muscle cells are rare, and there is always the problem of immune rejection when using someone else’s cells. And recent studies had also shown that hiPSCs derived from young and healthy people could be transformed into heart cells. It had not been seen whether hiPSCs could be derived from the elderly or diseased though. Or whether or not these new heart cells could integrate into the existing heart muscle.
Professor 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, who led the research, said: “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.”
The researchers took skin cells from two heart failure patients and reprogrammed them by delivering three genes, or ‘transcription factors’, and then a molecule called valproic acid, to the cell nucleus. Importantly, they left out a transcription factor called c-Myc, 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 tumours,” 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 that used a virus to deliver the reprogramming information to the nucleus, but that could be removed afterwords, to avoid insertional oncogenesis.
The hiPSCs created this way were just as effective at becoming heart muscle cells as the ones derived from the young, healthy, study controls.
The researchers then cultured the new heart tissues together with existing heart tissue, and within 1-2 days the cells were beating together.
“The tissue was behaving like a tiny microscopic cardiac tissue composed of approximately 1000 cells in each beating area,” said Prof Gepstein.
The heart tissue was then transplanted into healthy rat hearts, and the grafted tissue started to develop connections with the cells in the host tissue.
“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,” 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.”
“There are several obstacles to clinical translation,” said Prof Gepstein. “These 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 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.”