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New Embryonic Stem Cell
Signalling Pathways
Tuesday, 20 March 2007
A newly discovered small molecule called IQ-1 plays a key role in preventing
embryonic stem cells from differentiating into one or more specific cell
types, allowing them to instead continue growing and dividing indefinitely,
according to research performed by a team of scientists who have recently
joined the stem-cell research efforts at the Keck School of Medicine of the
University of Southern California. Their findings are being published today
in an early online edition of the Proceedings of the National Academy of
Sciences.
This discovery takes scientists another step closer to being able to grow
embryonic stem cells without the “feeder
layer” of mouse fibroblast cells that is essential for maintaining the
pluripotency of embryonic stem cells, says the study’s primary
investigator, Michael Kahn, Ph.D., who was recently named
the first Provost’s Professor of Medicine and Pharmacy at USC. Such a layer
is needed because it is currently the only proven method to provide the
stem cells with the necessary chemical signals that prompt them to stay
undifferentiated and to continue dividing over and over.
Still, growing human embryonic stem cells on a layer of mouse fibroblasts
has never made much sense to the scientists forced to do just that.
“Stem cells that grow on feeders are
contaminated with mouse glycoproteins markers,” Kahn
says.
“If you use them into humans, you’d
potentially have a horrible immune response.”
And so, in order to take any eventual stem cell-based treatments from the
laboratory to the clinic, there needs to be a way to keep the cells growing
and dividing without the use of mouse fibroblasts. The discovery of IQ-1,
says Kahn, is a significant step in that
direction.
What IQ-1 does, Kahn
explains, is to block one arm of a cell-signalling pathway called the Wnt
pathway, while enhancing the signal coming from the other arm of the Wnt
pathway. The Wnt pathway is known to have dichotomous effects on stem cells
i.e. both proliferative and differentiative. More specifically, IQ-1 blocks
the coactivator p300 from interacting with the protein ß-catenin; this
prevents the stem cells from being ‘told’ to differentiate into a more
specific cell type. At the same time, IQ-1 enhances the interaction between
the coactivator CBP and ß-catenin, which signals the cells to keep dividing
and to remain as fully potent stem cells.
“This way, you can essentially
maintain the stem cell’s growth and potency for as long as you want,” Kahn says.
The studies of IQ-1 and its effects reported in the newly published PNAS
paper were performed at the University of Washington in Seattle by Kahn and
his colleagues (along with collaborators from the Asahi Kasei Corporation
in Shizuoka, Japan) using mouse embryonic stem cells, but Kahn notes that
subsequent pilot studies using human embryonic stem cells, in collaboration
with Dr. Qilong Ying at the Centre for Stem Cell and Regenerative Medicine
at the Keck School of Medicine, have confirmed that IQ-1 plays a similar
role in that system as well.
“If we can create a totally
chemically defined system for growing human embryonic stem cells without any
risk of contamination, it would make life much easier for scientists than
it is at the moment,” says Kahn. “And that’s our goal.”
“Kahn's study provides us with
striking new insights into the molecular regulatory machinery inside
embryonic stem cells,” adds Martin
Pera, Ph.D., director of the Centre for Stem Cell and Regenerative
Medicine at the Keck School of Medicine.
“His team has identified a chemical that controls a critical switch that
enables stem cells to multiply indefinitely in the laboratory. These
findings will help lead to the development of new techniques to propagate
pure populations of embryonic stem cells on a large scale, an essential
prerequisite to the successful development of stem cell based therapies.”
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Reference:
“Wnt/ß-catenin/CBP signalling maintains long-term
murine embryonic stem cell pluripotency.”
Tomoyuki Miyabayashi,
Jia-Ling Teo, Masashi Yamamoto, Michael McMillan, Cu Nguyen and Michael
Kahn
PNAS Early Edition, Mar. 19, 2007, http://www.pnas.org.
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