Haifa scientists have adapted an innovative Japanese gene-implantation technique and succeeded in "turning back the clock" for human skin cells, reprogramming them into artificial embryonic stem cells and then switching them into heart cells in the lab.
Although implementing this clinically to repair damaged human hearts is at least a decade or two away, the Israeli accomplishment can already be utilized for in-depth study of genetic diseases and the development of personalized drugs for inherited disorders, such as those involving irregular heartbeat.
Prof. Lior Gepstein, a senior cardiologist at Rambam Medical Center and the Technion-Israel Institute of Technology's Rappaport Medical Faculty, heads a team of 12 that has just published its findings in the latest issue of the prestigious journal Circulation.
Nearly three years ago, Gepstein made headlines by creating beating cardiac tissue in the lab from human embryonic stem cells and bringing about the creation of tiny blood vessels within the tissue - which could eventually make it possible to implant the tissue in a diseased human heart.
The team's work is based on that of Prof. Shinya Yamanaka, a 47-year-old Japanese physician and stem cell researcher at Kyoto University.
In 2006, Yamanaka's team generated "induced pluripotent stem cells" (iPSCs) from adult mouse fibroblasts. This type of stem cell can be turned artificially into virtually any type of body cell - a characteristic that until then was only attributed to stem cells derived from tiny embryos - and at least theoretically could be used to repair damaged or diseased tissue.
The origin of the iPSCs was nonpluripotent adult mouse somatic (body) cells rather than embryos. Yamanaka injected four specially chosen mouse genes into the mouse skin cell to "force" the expression of these genes and give them new powers. This can now be done using only three genes.
By translating this research
into human cells, Gepstein's team could reduce scientists' dependence on embryos for stem-cell research. The controversial use of embryos led former US president George W. Bush to bar federal funding for studies using new cell lines.
Unlike Yamanaka, the Technion/Rambam team took adult skin cell fibroblasts from healthy individuals. In about three months, with funding from Israeli grants, the team "pushed" the adult cells "backward in time" so they became stem cells with the characteristics of pluripotent embryonic stem cells, and then pushed them forward into heart cells.
The four genes used to "reprogram" the adult skin cells were selected specially because they encourage cell division and protect embryonic stem cells.
Gepstein told The Jerusalem Post in an interview that the Japanese technique was being studied around the world and was one of the "hottest subjects" in stem cell research today.
"Almost every week, there is a new article on the subject in Nature or Science," Gepstein said.
He added that the rejuvenation of human cells and their transformation into iPSCs could be carried out in almost any human cell. If the reprogramming process is halted in the middle, the iPSCs turn back into ordinary somatic cells as if they were Cinderella's carriage turning back into a pumpkin, he explained. But the "trigger" genes could be removed from the cell without stopping the reprogramming process.
One of the hazards in the use of iPSCs and ordinary embryonic stem cells is that they could begin to divide wildly, making them cancerous, "so it will be years before they are used clinically," said Gepstein. "If the genes remain in the cell, there is more danger of a tumor and less if they are removed."
Work on rats and then pigs could eventually lead to clinical work, but scientists would have to learn how to make large amounts of the iPSCs, he said.
Among the genetic diseases that could eventually benefit from this research are single-gene mutations that cause irregular heartbeat, cardiomyopathies that weaken the heart muscle, familial dysautonomia, neurodegenerative disorders, Huntington's and even rare forms of epilepsy.
Another possible benefit is that unlike ordinary embryonic stem cells from a donor, which would be rejected if implanted into humans to repair tissue, if a person's own somatic cells containing mutations were taken and turned into iPSCs, they would not be rejected.
The iPSCs thus could eventually serve as a kind of "guinea pig" or model for testing drugs on patients' newly created heart cells, rather than removing cells from the patient's heart, which would be impossible.
Gepstein said he had been amazed when the Japanese made their discovery that "nature allowed this reprogramming through a back door. Even though it seemed very unlikely to succeed, it did."
The process is very expensive and takes a lot of time, "but I am optimistic that eventually it will lead to something," Gepstein said. "Even now, a US company, Geron, has received permission from the Food and Drug Administration to treat a spinal disease with embryonic stem cells."
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