To Members and Friends of the Los Angles Gerontology
hiPSC’s are a major stepping stone toward our agenda. What took us so
Should we throw more money at the problem or do we need more smart
people? Or both?
— Steve Coles
“Human Stem-Cell Clock Reset to
In this 3-D
rendering of confocal images, human embryonic stem cells (hESC’s)
are identified with a pluripotency marker (NANOG, in
reduced in reset cells.
[Wolf Reik and Gabriella Ficz, Babraham Institute]
September 12, 2014; (Genetic Engineering News) — Adult
stem cells are routinely taken back to early developmental states —
but not all the way back, not to the very start of human development.
Yes, under the manipulations of scientists, these cells can typically
induced to pluripotency, the ability to follow different developmental
Yet, these cells are not blank slates, i.e., they are not
They retain biases toward particular cell fates and tissue
their use in therapeutic applications, such as regenerative
“Almost zero” stem cells naturally vary.
Their developmental clocks
are not quite synchronized; their developmental biases differ in
Such variability has been built into stem-cell research, making it more
difficult to reconcile results from different studies.
All such complications may be swept aside, or
diminished, now that scientists from the Wellcome Trust, the
Babraham Institute, and the European Bioinformatics Institute
have found a way to reset human pluripotent stem cells to a pristine
state — a developmental state equivalent to cells found in an embryo
before it implants in the womb ([7 Â 9] days old).
The scientists achieved for human cells — a feat
to cells from mice and rats. Specifically, the scientists reverted
human cells to ground-state pluripotency. The scientists, however,
could not use the approach that has proven so reliable with mouse
cells. Although mouse cells respond to a protein called Leukemia
Inhibitory Factor (LIF), entering a state of naive pluripotency,
human cells did not.
To overcome this difficulty, the researchers took a
They used reprogramming methods to express two different genes,
NANOG and KLF-2. These genes, which needed to be expressed,
but only briefly, caused the network of genes that controls the cell
to “reboot” and induce the naive pluripotent state.
This finding appeared September 11th in the journal
Cell, in an
article entitled, “Resetting Transcription Factor Control Circuitry
toward Ground-State Pluripotency in Human.”
“Reset cells self-renew continuously without ERK
phenotypically stable, and are karyotypically intact,” wrote the
authors. “They differentiate in vitro and form teratomas
Metabolism is reprogrammed with activation of mitochondrial
respiration as in ESC. DNA methylation is dramatically reduced, and
transcriptome state is globally realigned across multiple cell
The reset human stem cells showed a loss of methyl
throughout the genome. Such marks, which accumulate during cell
development, are a form of epigenetic memory. By removing such
marks, the new procedure essentially wipes away epigenetic
memories, pushing the cells back to a more permissive state.
Without an epigenetic memory of their previous lineages, the cells
effectively achieved “blank slate” status and gained
potential to become any adult cell.
“Our findings suggest that it is possible to
rewind the clock
to achieve true ground-state pluripotency in human cells,” said
Prof. Austin Smith, Director of the Wellcome Trust — Medical
Research Council Stem Cell Institute. “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 may pave the way for the production of
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 specialized cell types for regenerative tissue
L. Stephen Coles, M.D., Ph.D., Cofounder
Los Angeles Gerontology Research GroupE-mail: firstname.lastname@example.orgE-mail: