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New study
reveals dynamic changes in gene regulation of human pluripotent stem cells
07-09-2012
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LA JOLLA, Calif.—In what they are calling "the most
comprehensive study of human pluripotent stem
cell variation to date," a team
of researchers from the Scripps
Research Institute and the University of
California, San Diego, has
discovered dynamic changes in gene regulation in
these cells, a finding that may have important implications for using them for
basic and clinical
research.
Human pluripotent stem cells (hPSCs) can give rise to
virtually every type of cell in
the body, and thus hold huge potential for cell
replacement therapies and drug development. But there is still much to be
learned about how these cells
behave in the lab, says Prof. Jeanne Loring of
Scripps Research, a lead author on a study recently published in the journal Cell Stem Cell.
Loring's lab focuses on basic and translational research
approaches to understanding stem cells at a molecular level, and its scientists
are
working to apply that knowledge in the field of regenerative medicine. Last
year, the team reported recurrent changes in the genomes of hPSCs as they are
expanded in culture, and their development of a technique for purifying cell
mixtures.
"One
of the big issues about using human pluripotent stem
cells for any kind of clinical application—including disease studies and drug
development—is that
these cells are unlike cells anyone has ever studied
before, and we must learn more about them. The first thing that came to mind
for us is that these
cells are like cancer cells in some ways. If one cell has
a slight survival advantage over others, as it grows and divides, this cell
will take over
the culture. The same thing happens in cancers, especially blood
cancers."
The team used tiny
beads to attach lectin to stem cells. The
cells that washed past were almost all non-stem cells, and the scientists
observed that both cell types could
be collected separately for use in research
or in treatments. This work presented a new way to solve purification and
safety problems in stem cell
research, says Loring.
"But we didn't answer the question of whether these changes
are close to
the genes involved in maintaining those cells as being
pluripotent," she notes. "The changes that occurred in culture were enhancing
that cell type.
That may or may not be a problem, but what is important is that
we pointed out that it happened."
Now, in a follow-up study that appears in the May 4 issue of
Cell Stem Cell, Loring's lab is
reporting that these cells can also
change their epigenomes, the patterns of
DNA modifications that regulate the activity of specific genes. These changes
may influence the cells'
abilities to serve as models of human disease and
development.
Specifically, the team assessed
the state of both DNA
methylation and gene expression in more than 200 hPSC samples from more than
100 cell lines, along with 80 adult cell samples
representing 17 distinct
tissue types. Both DNA methylation and demethylation are important regulatory
processes in cellular differentiation.
Key to the research was a new global DNA methylation array developed
in collaboration with Illumina Inc. that detects the methylation state of
450,000 sites in the
human genome. The results showed surprising changes in
patterns of DNA methylation in the stem cells. Because of the unprecedented
breadth of the
study, the researchers were able to determine the frequency of
different types of changes.
The
team observed that pluripotent cells differ from somatic
cells at sites in the genome that are generally considered to be epigenetically
stable—the
inactivated X chromosome in female cells and imprinted loci. X
chromosome inactivation (XCI) was not erased following the reprogramming of
human
fibroblasts, but was lost over time, leading to a loss of dosage
compensation of subsets of X chromosome genes. This includes a large number of
X-
linked disease genes, which may complicate a large number of hPSC-based
models of X-linked disease. Aberrations in genomic imprints are frequent in
hPSCs, and all of the hPSCs analyzed in this study had abberant DNA methylation
of at least one imprinted gene.
"There are whole families of diseases associated with
abnormal imprinting," says Loring. "We're probably going to find
that in a lot
of cases, neurodevelopmental diseases will have abnormalities in methylation
that we can trace to a mutated gene, and then use that as
leverage to try to
figure out how they are controlled."
Some diseases or conditions Loring
specifically mentions are
Rett's syndrome, Fragile X syndrome and even autism.
The
team is now working on controlling the imprinting and
which genes are turned on or off when cells differentiate.
"These are not small questions, but now we know that we need
to ask them," says Loring.
The results presented by her team are interesting from a
developmental biology perspective because "it places us on the edge
of
understanding the development of some diseases," Loring points out.
"When you think about
embryonic development, it all goes so
well, and it is hard for us to understand how all of these things can fall into
place," she says. "This
research will give us insight into how that happens.
This is the kind of thing we couldn't have done a year ago because we didn't
have the tools. I
feel like we are in an exciting place right now because we're
getting really good at culturing cells and doing bioinformatic analysis. The
combination
of these things is leading to interesting kinds of insights that
wouldn't have been possible before."
The study, "Recurrent Variations in DNA Methylation in Human
Pluripotent Stem Cells and their Differentiated Derivatives," was supported by
the California Institute for Regenerative Medicine and the U.S. National
Institutes of Health. Loring's colleagues on the multi-site
project included
Gulsah Altun, Candace Lynch, Ha Tran, Ileana Slavin, Ibon Garitaonandia,
Franz-Josef Müller, Yu-Chieh Wang, Francesca S. Boscolo and
Eyitayo Fakunle
from Scripps Research; Julie V. Harness and Hans S. Keirstead from the
University of California at Irvine; Mana M. Parast from the University of
California San Diego; Tsaiwei Olee and Darryl D.
D'Lima from Scripps Health; Biljana
Dumevska and Andrew L. Laslett from the Commonwealth Scientific and Industrial
Research Organization in Australia; Uli Schmidt from the Stem Cell Laboratory
in Sydney, Australia; Hyun
Sook Park and Sunray Lee from the Laboratory of Stem
Cell Niche in
Seoul, South Korea; Ruslan Semechkin from International
Stem Cell
Corp.; and Vasiliy Galat from Children
's Memorial Research Center in Chicago.
Code: E07111203 Back |
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