While the field of human embryonic stem cell research
receives a tremendous amount of public attention, many scientists are also
exploring the potential of adult stem cells for possible therapies. But this
field raises other difficulties. Although adult stem cell research isn’t
fraught with the controversies that surround embryonic stem cells, adult stem
cells are extremely difficult to isolate and then to multiply in a lab dish.
Now, as reported in the May 6 issue of the journal Cell, researchers in the
lab of Whitehead Institute Member Rudolf Jaenisch have discovered a mechanism
that might enable scientists to multiply adult stem cells quickly and
efficiently.
"These findings provide us with a new way of looking at adult stem cells and
for possibly exploiting their therapeutic potential," says Jaenisch, who also
is a professor of biology at MIT. This research focuses on a gene called Oct4,
a molecule that is known to be active in the early embryonic stage of an
organism. Oct4’s primary function is to keep an embryo in an immature state.
It acts as a gatekeeper, preventing the cells in the embryo from
differentiating into tissue-specific cells. While Oct4 is operating, all the
cells in the embryo remain identical, but when Oct4 shuts off, the cells begin
growing into, say, heart or liver tissue.
Konrad Hochedlinger, a post-doctoral researcher in Jaenisch’s lab, was
experimenting with the Oct4 gene, curious to see what happens in laboratory
mice when the gene is reactivated in adult tissue where it has long been
dormant. Hochedlinger found that when he switched the gene on, the mice
immediately formed tumors in the gut and in the skin where the gene was
active. When he switched the gene off, the tumors subsided, demonstrating that
the process is reversible.
Discovering that simply flipping a single gene on and off has such an
immediate effect on a tumor was unexpected, even though Oct4 is known to be
active in certain forms of testicular and ovarian cancer. Still, the most
provocative finding was that "Oct4 causes tumors by preventing adult stem
cells in these tissues from differentiating," says Hochedlinger. In other
words, with Oct4 active, the stem cells could replicate themselves
indefinitely, but could not produce mature tissue.
One of the main obstacles with adult stem cell research is that, in order for
these cells to be therapeutically useful, researchers need to multiply them in
the lab. But when adult stem cells are isolated, they immediately start
growing into their designated tissue type. It would be ideal if scientists had
a way to take a liver adult stem cell and multiply it in a dish without having
it form mature liver tissue.
This experiment showed that when Oct4 was reactivated, the adult stem cells in
those tissues continued to replicate without forming mature tissue. In a
mammal’s body, this type of cell behavior causes tumors. But under the right
laboratory conditions, it could be a powerful tool. "This may allow you to
expand adult stem cells for therapy," observes Hochedlinger. "For instance,
you could remove a person’s skin tissue, put it in a dish, isolate the skin
stem cells, then subject it to an environment that activates Oct4. This would
cause the cells to multiply yet remain in their stem cell state. And because
this process is reversible, after you have a critical mass of these cells, you
can then place them back into the person where they would grow into healthy
tissue." "This could be very beneficial for burn victims," Jaenisch adds.
Researchers in his lab are also exploring whether activating Oct4 in somatic
cells, such as skin cells, would make it easier for these cells to be
reprogrammed when used as donors for nuclear transplantation. If so, it may
help scientists more efficiently "customize" embryonic stem cells that could
be used to treat diseases such as diabetes or Parkinson’s.
Written by David Cameron.
To receive a copy of this paper, please contact
newsroom@wi.mit.edu.
Full citation
Cell, Vol 121, 465-477, May 6, 2005.
“Ectopic Expression of Oct-4 Blocks Progenitor-Cell Differentiation and Causes
Dysplasia in Epithelial Tissues.”
Authors: Hochedlinger, K., Yamada, Y., Beard, C., and Jaenisch, R.
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts