SCIENTISTS REVERT HUMAN STEM CELLS TO PRISTINE STATE
Researchers at
EMBL-EBI have resolved a long-standing challenge in stem cell biology by
successfully 'resetting' human pluripotent stem cells to a fully pristine
state, at point of their greatest developmental potential. The study, published
in Cell, involved scientists from the UK, Germany and Japan and was led jointly
by EMBL-EBI and the University of Cambridge.
Embryonic stem (ES)
cells, which originate in early development, are capable of differentiating
into any type of cell. Until now, scientists have only been able to revert
'adult' human cells (for example, liver, lung or skin) into pluripotent stem
cells with slightly different properties that predispose them to becoming cells
of certain types. Authentic ES cells have only been derived from mice and rats.
"Reverting mouse
cells to a completely 'blank slate' has become routine, but generating
equivalent naïve human cell lines has proven far more challenging," says
Dr Paul Bertone, Research Group Leader at EMBL-EBI and a senior author on the
study. "Human pluripotent cells resemble a cell type that appears slightly
later in mammalian development, after the embryo has implanted in the
uterus."
At this point, subtle
changes in gene expression begin to influence the cells, which are then
considered 'primed' towards a particular lineage. Although pluripotent human
cells can be cultured from in vitro fertilised (IVF) embryos, until now there
have been no human cells comparable to those obtained from the mouse.
Wiping cell memory
"For years, it
was thought that we could be missing the developmental window when naïve human
cells could be captured, or that the right growth conditions hadn't been
found," Paul explains. "But with the advent of iPS cell technologies,
it should have been possible to drive specialised human cells back to an
earlier state, regardless of their origin -- if that state existed in
primates."
Taking a new approach,
the scientists used reprogramming methods to express two different genes, NANOG
and KLF2, which reset the cells. They then maintained the cells indefinitely by
inhibiting specific biological pathways. The resulting cells are capable of
differentiating into any adult cell type, and are genetically normal.
The experimental work
was conducted hand-in-hand with computational analysis.
"We needed to
understand where these cells lie in the spectrum of the human and mouse
pluripotent cells that have already been produced," explains Paul.
"We worked with the EMBL Genomics Core Facility to produce comprehensive transcriptional
data for all the conditions we explored. We could then compare reset human
cells to genuine mouse ES cells, and indeed we found they shared many
similarities."
Together with
Professor Wolf Reik at the Babraham Institute, the researchers also showed that
DNA methylation (biochemical marks that influence gene expression) was erased
over much of the genome, indicating that reset cells are not restricted in the
cell types they can produce. In this more permissive state, the cells no longer
retain the memory of their previous lineages and revert to a blank slate with
unrestricted potential to become any adult cell.
Unlocking the
potential of stem cell therapies
The research was
performed in collaboration with Professor Austin Smith, Director of the
Wellcome Trust-Medical Research Council Stem Cell Institute.
"Our findings
suggest that it is possible to rewind the clock to achieve true ground-state
pluripotency in human cells," said Professor Smith. "These cells may
represent the real starting point for formation of tissues in the human embryo.
We hope that in time they will allow us to unlock the fundamental biology of
early development, which is impossible to study directly in people."
The discovery paves
the way for the production of superior patient material for translational
medicine. Reset cells mark a significant advance for human stem cell
applications, such as drug screening of patient-specific cells, and are
expected to provide reliable sources of specialised cell types for regenerative
tissue grafts.
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