Recipe for cell reprogramming adds protein
Embryonic-like stem cells can be created without cancer-causing gene
CAMBRIDGE, Mass. (August 6, 2008) – A drug-like molecule called Wnt
can be substituted for the cancer gene c-Myc, one of four genes added
to adult cells to reprogram them to an embryonic-stem-
state, according to Whitehead researchers. Researchers hope that such
embryonic stem-cell-like cells, known as induced pluripotent (IPS)
cells, eventually may treat diseases such as Parkinson's disease and
diabetes.
Demonstrated in mice, the elimination of c-Myc represents an
important step in creating IPS cells in a manner that in the future
may be applied to human therapeutics.
"This is a good sign for the possible replacement of the other three
genes used to reprogram cells," says Ruth Foreman, a MD/PhD student
in the lab of Whitehead Member Rudolf Jaenisch and a lead co-author
on the paper, published online in Cell Stem Cell on August 6. The
other lead co-authors are Alex Marson, an MD/PhD student in the labs
of Jaenisch and Whitehead Member Richard Young, and Brett Chevalier,
a research scientist in the Young lab.
"IPS cells hold great potential for future medicine, but we must
learn how to generate these cells in a manner that is safe for
clinical therapies," says Young, who is also a professor of biology
at Massachusetts Institute of Technology. "This advance in
reprogramming is one key step toward that goal,"
Currently, IPS cells can be created by reprogramming adult cells
through the use of viruses to transfer four genes (Oct4, Sox2, c-Myc
and Klf4) into the cells' DNA. The activated genes then override the
adult state and convert the cells to embryonic-like IPS cells.
However, this method poses significant risks for potential use in
humans.
First, the viruses employed in the process, called retroviruses, are
associated with cancer because they insert DNA anywhere in a cell's
genome, thereby potentially triggering the expression of cancer-
causing genes, or oncogenes. Second, c-Myc is a known oncogene whose
overexpression can also cause cancer. For IPS cells to be employed to
treat human diseases such as Parkinson's, researchers must find safe
alternatives to reprogramming with retroviruses and oncogenes.
Earlier research has shown that c-Myc is not strictly required for
the generation of IPS cells. However, its absence makes the
reprogramming process time-consuming and highly inefficient.
To bypass these obstacles, the Whitehead researchers replaced c-Myc
and its retrovirus with a naturally occurring signaling molecule
called Wnt3a. When added to the fluid surrounding the cells being
reprogrammed, Wnt3a promotes the conversion of adult cells into IPS
cells.
"We're not sure if the Wnt molecule is doing the same thing as c-Myc
or complementing c-Myc's activity," says Chevalier. "But it does
increase stem cell growth similar to c-Myc."
"This is a good start toward using external cues instead of genetic
manipulation to reprogram cells," says Marson. "But we still need to
eliminate the need for retroviruses for the three other genes."
Although the technique is promising in mouse cells, its potential
applications in humans have not been studied, emphasizes Jaenisch,
who is also a professor of biology at MIT. "Is the same pathway
acting in the human system and can Wnt molecules be used to reprogram
human cells?" he asks. "We don't know, but I think those are very
important questions to investigate.
###
This research was supported by the National Institutes of Health.
Written by Nicole Giese
Rudolf Jaenisch and Richard Young's primary affiliations are with
Whitehead Institute for Biomedical Research, where their laboratories
are located and all their research is conducted. Jaenisch and Young
are also professors of biology at Massachusetts Institute of
Technology.
Full citation:
Cell Stem Cell August 7, 2008 (online August 6, 2007).
Wnt stimulation substitutes for c-Myc in reprogramming somatic cells
to induced pluripotent stem cells
Alexander Marson (1,2), Ruth Foreman (1,2), Brett Chevalier (1),
Michael Kahn (3,4), Richard A. Young (1,2), Rudolf Jaenisch (1,2).
Whitehead Institute for Biomedical Research, 9 Cambridge Center,
Cambridge, Massachusetts 02142, USA.
Department of Biology, Massachusetts Institute of Technology (MIT),
Cambridge, Massachusetts 02139, USA.
Institute for Stem Cell and Regenerative Medicine, University of
Southern California, Los Angeles, California 90033, USA.
Department of Biochemistry and Molecular Biology, University of
Southern California, Los Angeles, California 90033, USA.
http://www.eurekale
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