A New Way Opened for Turning Fibroblasts Directly into Endothelial Cells
A New Way Opened for Turning Fibroblasts Directly into Endothelial Cells
Korean research team at Seoul National University Hospital found out for the first time in the world that adult fibroblasts can be directly transformed into endothelial cells without going through the stage of induced pluripotent stem cells.
The finding is expected to serve as a remarkable milestone in the treatment of cardiovascular diseases as it opened up a possibility of cardiovascular regeneration by using skin fibroblasts.
The research team led by Professor Hyo-Soo Kim and Jung-Kyu Han at the Department of Internal Medicine at Seoul National University Hospital showed for the first time how to efficiently transdifferentiate skin fibroblasts into endothelial cells without going through the process of turning skin fibroblasts into induced pluripotent stem cells and differentiating them again into endothelial cells.
As a way to revive healthy blood vessel, research so far has been focusing on differentiating embryonic stem cells or induced pluripotent stem cells (reprogrammed pluripotent stem cells) into endothelial cells. This approach, however, had its limitation as it was not only ethically controversial but had the risk of developing tumor and being contaminated by feeder cells during cultivation and required highly complicated culture technique. The research team overcame such obstacles by succeeding in differentiating skin fibroblasts directly into endothelial cells.
The research team first separated fibroblast from the skin of a laboratory mouse. Then they let eleven genes, which play an important role in forming endothelial cells during embryogenesis, to be overly expressed by using viruses.
In the meantime, the team found out that Tie2, an endothelial-specific marker, was expressed in some of the fibroblasts whose eleven genes have been overly expressed. They next determined five key factors among the eleven candidates for the most efficient and effective induction of Tie 2.
The fibroblast whose five genes were overly expressed soon had its appearance transformed so similar to endothelial cells, which the research team called induced endothelial cells (iECs).
These iECs showed endothelial characteristics, and demonstrated genetic profile similar to endothelial cells. Further, iECs formed capillary vessels on the culture dish. The research team tied up leg arteries of the laboratory mice to cause ischemia and separated them into two groups. After injecting one group with fibroblasts (control group) and the other with induced endothelial cells (experimental group), blood vessel formation and blood flow recovery of the two groups were compared.
The result was that the experimental group had their blood flow recovery two times faster than the control group because the injected induced endothelial cells formed new vessels. The finding was confirmed by microscopic examination using fluorescence staining.
According to the data released by Statistics Korea last year, heart diseases ranked second as a death cause among Koreans. Among them, ischemic heart diseases such as angina and myocardial infarction had the highest proportion. Coronary intervention using stent, coronary artery bypass surgery, and medication have been used for treating the diseases. However, those modalities are far from a fundamental treatment which get the diseased vessel back to healty ones.
Professor Hyo-Soo Kim said, “The research is a remarkable achievement that paved the way for greater insight into the molecular understanding of transdifferentiation.” He added, “The research will bring tremendous transformation into the blood vessel regeneration treatment as we will be able to generate massive amounts of endothelial cells directly from fibroblasts that we can easily acquire from patients. It will also serve as a significant breakthrough for the ongoing project of establishing the National Stem Cell Bank.”
The research was introduced by Professor Jung-Kyu Han on November 2013 during the annual symposium hosted by the American Heart Association. It was also selected as one of the most outstanding research achievements of the year at AHA Daily News, a medical journal officially published by the symposium.