New insights into cellular reprogramming revealed by genomic analysis
30.05.2008
Research collaboration of Harvard, Whitehead Institute, and Broad
Institute uncovers critical molecular events underlying reprogramming
of differentiated cells to a stem cell state
The ability to drive somatic, or fully differentiated, human cells
back to a pluripotent or "stem cell" state would overcome many of the
significant scientific and social challenges to the use of embryo-
derived stem cells and help realize the promise of regenerative
medicine.
Recent research with mouse and human cells has demonstrated that such
a transformation ("reprogramming"
process is inefficient and, when it does work, poorly understood. But
now, thanks to the application of powerful new integrative genomic
tools, a cross-disciplinary research team from Harvard University,
Whitehead Institute, and the Broad Institute of MIT and Harvard has
uncovered significant new information about the molecular changes
that underlie the direct reprogramming process. Their findings are
published online in the journal Nature.
"We used a genomic approach to identify key obstacles to the
reprogramming process and to understand why most cells fail to
reprogram," said Alexander Meissner, assistant professor at Harvard
University's Department of Stem Cell and Regenerative Biology and
associate member of the Broad Institute, who led the multi-
institutional effort. "Currently, reprogramming requires infecting
somatic cells with engineered viruses. This approach may be
unsuitable for generating stem cells that can be used in regenerative
medicine. Our work provides critical insights that might ultimately
lead to a more refined approach."
Previous work had demonstrated that four transcription factors —
proteins that mediate whether their target genes are turned on or
off — could drive fully differentiated cells, such as skin or blood
cells, into a stem cell-like state, known as induced pluripotent stem
(iPS) cells. Building off of this knowledge, the researchers examined
both successfully and unsuccessfully reprogrammed cells to better
understand the complex process.
"Interestingly, the response of most cells appears to be activation
of normal `fail safe' mechanisms", said Tarjei Mikkelsen, a graduate
student at the Broad Institute and first author of the Nature
paper. "Improving the low efficiency of the reprogramming process
will require circumventing these mechanisms without disabling them
permanently.
The researchers used next-generation sequencing technologies to
generate genome-wide maps of epigenetic modifications — which control
how DNA is packaged and accessed within cells — and integrated this
approach with gene expression profiling to monitor how cells change
during the reprogramming process. Their key findings include:
Fully reprogrammed cells, or iPS cells, demonstrate gene expression
and epigenetic modifications that are strikingly similar, although
not necessarily identical, to embryonic stem cells.
Cells that escape their initial fail-safe mechanisms can still
become `stuck' in partially reprogrammed states.
By identifying characteristic differences in the epigenetic maps and
expression profiles of these partially reprogrammed cells, the
researchers designed treatments using chemicals or RNA interference
(RNAi) that were sufficient to drive them to a fully reprogrammed
state.
One of these treatments, involving the chemotherapeutic 5-
azacytidine, could improve the overall efficiency of the
reprogramming process by several hundred percent.
"A key advance facilitating this work was the isolation of partially
reprogrammed cells," said co-author Jacob Hanna, a postdoctoral
fellow at the Whitehead Institute, who recently led two other
independent reprogramming studies. "We expect that further
characterization of partially programmed cells, along with the
discovery and use of other small molecules, will make cellular
reprogramming even more efficient and eventually safe for use in
regenerative medicine."
Nicole Davis | Quelle: EurekAlert!
Weitere Informationen: www.broad.mit.
www.harvard.
www.wi.mit.edu
http://www.innovati
report.de/html/
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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