After years of promise but limited results, stem cell research has suddenly exploded with a dramatic series of breakthroughs.
- November 20, 2007. Shinya Yamanaka and his Kyoto University team reported that a simple recipe of four genes can transform adult human cells into cells that resemble embryonic stem cells. On the same day, a team from the University of Wisconsin, Madison, led by biologist James Thomson, who first found human embryonic stem cells in 1998, reported similar findings.
- November 30. Dr. Yamanaka reported that the recipe is even simpler, just three ingredients. The gene deleted from the recipe was an oncogene that can cause cancer. By showing that it is not needed, his team took one more step to making stem cells practical.
- December 6. Rudolf Jaenish at MIT reported that his team had used the stem cell–like cells to “cure” sickle-cell anemia in mice.
The groundwork for these rapid advances was laid by Dr. Yamanaka in 2006, when he first described the process for making “induced pluripotent stem (iPS) cells” in mice. “Pluripotent” refers to the ability to differentiate into most other cell types. His team discovered a simple recipe of just four ingredients that can transform adult human skin cells into cells resembling embryonic stem cells. The converted cells have many of the physical, growth, and genetic features typically found in embryonic stem cells and can differentiate to produce other tissue types, including neurons and heart tissue.
The Yamanaka team added, however, that a comprehensive screen of the activity of more than 30,000 genes showed that the iPS cells are similar, but not necessarily identical, to embryonic stem cells.
Dr. Yamanaka's findings have done more than accelerate stem cell research. They also provide a method that sidesteps the ethical stumbling blocks of stem cells obtained from human embryos. He emphasized, however, that it would be “premature to conclude that iPS cells can replace embryonic stem cells.”
Embryonic stem cells, derived from the inner cell mass of mammalian blastocysts–balls of cells that develop after fertilization and go on to form a developing embryo–have the ability to grow indefinitely while maintaining pluripotency, the researchers explained. Those properties have led to expectations that human embryonic stem cells might have many scientific and clinical applications, most notably the potential to treat patients with various diseases and injuries, such as juvenile diabetes and spinal cord injury.
The use of human embryos, however, faces ethical controversies that hinder the applications of human embryonic stem cells, they continued. In addition, it is difficult to generate patient- or disease-specific embryonic stem cells, which are required for their effective application. One way to circumvent these issues is to induce pluripotent status in other cells of the body by direct reprogramming, Shinya said.
|
|
Last year, the Yamanaka team found that four factors, known as Oct3/4, Sox2, c-Myc, and Klf4, could confer upon differentiated fibroblast cells from embryonic or adult mice the pluripotency normally reserved for embryonic stem cells. Fibroblasts make up structural fibers found in connective tissue. Those four factors are “transcription factors,” meaning that they control the activity of other genes. They were also known to play a role in early embryos and embryonic stem cell identity. Further study showed that c-Myc was not necessary for the induction process, so it was not included in the final “recipe.”
The researchers have now shown that the same factors can generate iPS cells from fibroblasts taken from human skin. “From about 50,000 transfected human cells, we obtained approximately 10 iPS cell clones,” Shinya said. “This efficiency may sound very low, but it means that from one experiment, with a single 10-centimeter dish, you can get multiple iPS cell lines.”
The iPS cells were indistinguishable from embryonic stem cells in terms of their appearance and behavior in cell culture, they found. They also express genetic markers that are used by scientists to identify embryonic stem cells. Human embryonic stem cells and iPS cells display similar patterns of global gene activity.
They showed that the converted human cells could differentiate to form three “germ layers” in cell culture. Those primary germ layers in embryos eventually give rise to all the body’s tissues and organs. They further showed that the human iPS cells could give rise to neurons using a method earlier demonstrated for human embryonic stem cells. The iPS cells could also be made to produce cardiac muscle cells, they found. Indeed, after 12 days of differentiation, clumps of cells in the laboratory dishes started beating.
When injected under the skin of mice, the human iPS cells produced tumors after 9 weeks. Those tumors contained various tissues, including gut-like epithelial tissue, striated muscle, cartilage, and neural tissue. They finally showed that iPS cells can also be generated in the same way from other human cells.
“We should now be able to generate patient- and disease-specific iPS cells, and then make various cells, such as cardiac cells, liver cells, and neural cells,” Shinya said. “These cells should be extremely useful in understanding disease mechanisms and in screening for effective and safe drugs. If we can overcome safety issues, we may be able to use human iPS cells in cell transplantation therapies.”
|
