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 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."
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."
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Article adapted by Medical News Today
from original press release.
----------------------------
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
Source: Cristin Carr
Whitehead
Institute for Biomedical Research
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