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Fully mature, differentiated B
cells can be reprogrammed to an embryonic-stem-cell-like state, without
the use of an egg, according to a study published in the April 18 issue
of Cell. In previous research, induced
pluripotent stem (IPS) cells typcially have been created from
fibroblasts, a specific type of skin cells that may differentiate into
other types of skin cells. Because there is no way to tell if the
fibroblasts were fully differentiated, the cells used in earlier
experiments may have been less differentiated and therefore easier to
convert to the embryonic-stem-cell-like state of IPS cells.
B
cells are immune cells that can bind to specific antigens, such as
proteins from bacteria, viruses or microorganisms. Unlike fibroblasts,
mature B cells have a specific part of their DNA cut out as a final
maturation step. “Once that piece of DNA is cut out, it can’t come
back,” says Jacob Hanna, first author on the paper and a postdoctoral
fellow in Whitehead Member Rudolf Jaenisch’s lab. “Checking the genome
give us a way to make sure the resulting IPS cells were not from
immature cells.”
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"In
principle, this will allow you to transfer a complex genetic human
disease into a Petri dish, and study it," says Whitehead Member Rudolf
Jaenisch. "That could be the first step to analyze the disease and to
define a therapy.”
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Hanna
and his colleagues began the experiment by generating IPS cells from
immature B cells. Similar to the process used to create IPS cells from
fibroblast cells, Hanna successfully reprogrammed the immature B cells
into IPS cells by using retroviruses to transfer four genes (Oct4,
Sox2, c-Myc and Klf4) into the cells’ DNA.
However,
an additional factor, CCAAT/enhancer-binding-protein-α (C/EBPα), was
needed to nudge mature B cells to be reprogrammed as IPS cells.
Like
IPS cells from earlier fibroblast studies, the IPS cells from both the
mature and immature B cells could be used to create mice. The mice
grown from the reprogrammed mature B cells were missing the same part
of their DNA as the mature B cells, demonstrating that Hanna and his
colleagues had successfully reprogrammed fully differentiated cells.
In
addition to demonstrating the power of reprogramming, this work offers
the promise of powerful new mouse models for autoimmune diseases such
as multiple sclerosis and type 1 diabetes, in which the body attacks
certain types of its own cells. For example, mature B or T cells
specific for nerve cells called glia could be reprogrammed to IPS cells
and then used to create mice with an entire immune system that is
primed to only attack the glia cells, thereby creating a mouse model
for studying multiple sclerosis.
Eventually,
researchers will be able to study diseases by following a similar
process with human cells, predicts Jaenisch, who is also a professor of
biology at Massachusetts Institute of Technology. “In principle, this
will allow you to transfer a complex genetic human disease into a Petri
dish, and study it,” he says. “That could be the first step to analyze
the disease and to define a therapy.”
This research was supported by the National Institutes of Health and the Helen Hay Whitney Foundation.
Written by Nicole Giese.
* * *
Rudolf
Jaenisch's primary affiliation is with Whitehead Institute for
Biomedical Research, where his laboratory is located and all his
research is conducted. He is also a professor of biology at
Massachusetts Institute of Technology.
* * *
Full Citation:
Cell, April 18, 2008 134(2)
"Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency"
Jacob
Hanna (1), Styliani Markoulaki (1), Patrick Schorderet (1), Caroline
Beard (1), Bryce W. Carey (1), Marius Wernig (1), Menno P. Creyghton
(1), Eveline J. Steine (1), (1), John P. Cassady (1), Christopher J.
Lengner (1), Jessica A. Dausman (1), Rudolf Jaenisch (1,2)
1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142 USA
2. Department of Biology, MIT, Cambridge, MA 02142 USA
Whitehead Institute for Biomedical Research
is a nonprofit, independent research and educational
institution. Wholly independent in its governance, finances
and research programs, Whitehead shares a close affiliation
with Massachusetts Institute of Technology through its
faculty, who hold joint MIT appointments.
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