Simple recipe that makes human skin cells mimic embryonic stem cells
could make cloning obsolete
20 November 2007 Japanese researchers have discovered a simple chemical
recipe that makes human skin cells act like embryonic stem cells. The new
technique could make obsolete the cloning method that produced Dolly the
sheep, the first animal to be cloned from an adult cell. Professor Ian
Wilmut of Edinburgh University, who created Dolly, already announced last
week that he is abandoning cloning and adopting the new method. The
converted skin cells from the new technique 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, according to the researchers. A comprehensive screen of the
activity of more than 30,000 genes showed that the so-called “induced
pluripotent stem (iPS) cells” are similar, but not identical, to embryonic
stem cells. "Pluripotent" refers to the ability to differentiate into most
other cell types. The research was published in an early publication of
the journal Cell, a publication of Cell Press.
The chemical cocktail used in the new study is identical to one the team
showed could produce iPS cells from adult mouse cells in another Cell
report last year. That came as a surprise, said Shinya Yamanaka of Kyoto
University in Japan, because human embryonic stem cells differ from those in
mice. Those differences had led them to suspect "that some other factors
might be required to generate human iPS cells,” he said. The findings are
an important step forward in the quest for embryonic stem cell-like cells
that might sidestep 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, Yamanaka said. Last year, his team found that four
factors, known as Oct3/4, Sox2, c-Myc, and Klf4, could lend differentiated
fibroblast cells taken from embryonic or adult mice the pluripotency
normally reserved for embryonic stem cells. Fibroblasts make up structural
fibres found in connective tissue. Those four factors are 'transcripton
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.
The researchers have now shown that the same four 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,” Yamanaka said.
“This efficiency may sound very low, but it means that from one experiment,
with a single ten centimeter dish, you can get multiple iPS cell lines.”
The iPS cells were indistinguishable from embryonic stem cells in terms of
their appearance and behaviour 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. The human iPS cells injected under the
skin of mice produced tumours after nine weeks. Those tumours 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,” Yamanaka said.
“These cells should be extremely useful in understanding disease mechanisms
and screening effective and safe drugs. If we can overcome safety issues, we
may be able to use human iPS cells in cell transplantation therapies.”
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