Beating heart muscle created from heart patients' skin
Scientists have for the first time been able to take skin cells from heart patients and turn them into healthy heart muscle cells that can integrate with existing heart tissue.
The research means it could be possible to treat heart failure patients with their own, human-induced pluripotent stem cells (hiPSCs) in as little as five years' time, avoiding the problem of the patients' immune systems rejecting the cells as 'foreign'.
HiPSCs from young and healthy people have been transformed into heart cells before, and heart scar tissue has been reprogrammed into healthy tissue.
But this is the first time tissue from elderly and diseased patients has been used, and the first time that heart cells created from hiPSCs have been integrated 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," says Professor Lior Gepstein of the Technion-Israel Institute of Technology and Rambam Medical Center.
The team took skin cells from two male heart failure patients, 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.
Importantly, they didn't include a transcription factor called c-Myc, which has been used for creating stem cells but which is known to cause cancer.
"One of the obstacles to using hiPSCs clinically in humans is the potential for the cells to develop out of control and become tumours," says 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 method - a virus that delivered reprogramming information to the cell nucleus but which could be removed afterwards.
And, they found, the resulting hiPSCs were able to develop into heart muscle cells, or cardiomyocytes, just as well as those that had come from healthy, young volunteers.
The researchers cultured the resultingheart muscle tissue, together with pre-existing cardiac tissue. Within as little as 24 hours, the tissues were beating together.
"The tissue was behaving like a tiny microscopic cardiac tissue composed of approximately 1,000 cells in each beating area," says Gepstein.
Finally, the new tissue was transplanted into healthy rat hearts, where it started to establish connections with the cells in the host tissue.
So far, the team has been able only to transplant human cells into animals, which then need to be treated with immunosuppressive drugs so that the cells aren't rejected.
It could take another five to ten years before the results can be translated into treatment for heart failure patients in the clinic, says Gepstein.
"There are several obstacles to clinical translation," he says.
"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."