Skin Cells From Heart Failure Patients Made Into Healthy New Heart Muscle Cells

Date: May-25-2012For the first time in medical science, Israeli scientists have successfully turned skin cells from heart failure patients into healthy new heart muscle cells.

This achievement is significant, as it opens up the prospect of treating heart failure patients with their own, human-induced pluripotent stem cells (hiPSCs) to fix their damaged hearts.

Furthermore, the cells would avoid being rejected as foreign as they would be derived from the patients themselves. The study is published in the European Heart Journal.
However, the researchers state that it could take a minimum of 5 to 10 years before clinical trials could start due to the many obstacles that must be overcome before using hiPSCs in humans is possible.

Although there has been advances in stem cell biology and tissue engineering, one of the major problems scientists have faced has been lack of good sources of human heart muscle cells and rejection by the immune system. Furthermore, until now, scientific have been unable to demonstrate that heart cells created from hiPSCs could integrate with existing cardiovascular 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 health and young - the equivalent to the stage of his heart cells when he was just born," said 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 study.

In the study, Professor Gepstein, Ms Limor Zwi-Dantsis, and their colleagues retrieved skin cells from two male heart failure patients, aged 51 and 61 years, and reprogrammed the cells by delivering 3 transcription factors (Sox2, Oct4, and Klf4) in addition to a small molecule called valproic acid, to the cell nucleus. The team did not include a transcription factor called c-Myc as it is a known cancer-causing gene.

Professor Gepstein said:

"One of the obstacles to using hiPSCs clinically in humans is the potential for the cells to develop out of control and become tumors. 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."

In addition, the team used an alternative strategy involving a virus transferred reprogramming data to the cell nucleus. However, the team removed the virus after the information had been transferred in order to avoid insertional oncogenesis.

The researchers found that 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.

The team then integrated the new heart muscle cells with existing heart tissue and found that they began beating together within 24-48 hours.

Professor Gepstein explained: "The tissue was behaving like a tiny microscopic cardiac tissue comprised of approximately 1000 cells in each beating area."

After the new tissue was transplanted into the hearts of healthy rats the team found that the grafted tissue began to establish connections with the cells in the host tissue.

Professor Gepstein said:

"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.

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."

He continues:

"There are several obstacles to clinical translation. 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 endeavor. I assume it will take at least five to ten years to clinical trials if one can overcome these problems."

Written By Grace Rattue

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