THE discovery two years ago of a technique for creating an immortal line of
human embryonic stem cells (ESCs) raised hopes that it would one day be possible
to grow endless supplies of specialised cells, or even organs for transplants.
But researchers are still puzzling over the exact biochemical signals needed to
control stem cells.
A key step on that road has now been taken with a study of mouse ESCs, which
shows that different levels of a “gatekeeper†protein called Oct-3/4 steer the
cells towards becoming placenta, body tissues or another generation of ESCs.
“The Oct-3/4 work tells us we are going to figure all this out,†says Ron McKay
of the US National Institutes of ÎçÒ¹¸£Àû1000¼¯ºÏ. “This is a technology, not a stab in
the dark,†says McKay. ESCs “are going to become a central part of modern
³¾±ð»å¾±³¦¾±²Ô±ðâ€.
A mind-boggling array of protein signals turns ESCs into the specialised
cells of the body. What’s more, to get the millions of cells that would be
needed for each transplant, researchers must find an easier way to grow human
ESCs. At the moment, human ESCs will only multiply if they are mixed with mouse
cells. They also have a tendency to go backwards in development, turning into
trophectoderm— cells that become placenta. Understanding what makes ESCs
multiply is the first stage in solving those problems.
Advertisement
Austin Smith of the University of Edinburgh and Hitoshi Niwa of Osaka
University in Japan suspected that Oct-3/4—a transcription factor protein,
which regulates gene activity—might be involved. They genetically
engineered mouse ESCs to produce different levels of Oct-3/4. Their results
showed that a finely tuned amount of the protein locks mouse ESCs into a state
where they multiply without becoming specialised. When the researchers turned up
the amount of Oct-3/4, the cells switched identities into mesoderm and primitive
endoderm—tissues that spawn body cells and the embryo’s yolk sac. When
they turned it down, the ESCs became trophectoderm. The team has licensed this
technique to the biotech company Stem Cell Sciences in Australia.
In a separate development, Martin Pera and his colleagues at Monash
University in Melbourne and the National University of Singapore have become
only the second team to establish an immortal line of human ESCs, and have
followed the cells’ differentiation into primitive muscle and nerve cells. The
reason it has taken two years to replicate the original finding is due in part
to regulations that limit human embryo research in many countries. Such research
is legal in Singapore.
Pera’s team also showed that human ESCs make Oct-3/4, which some researchers
had doubted. Taken together, the findings hint at a possible reason for some of
the problems with human ESC cultures: varying levels of Oct-3/4 may be stopping
the ESCs from multiplying. “It’s an absolutely key issue, particularly because
human ESCs tend to differentiate into trophectoderm,†says Smith.

-
Sources:
Nature Genetics (vol 24, p 372) - Nature Biotechnology (vol 18, p 399)