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September 12, 2014

Human Stem Cell Clock Reset to Zero

In this 3D rendering of confocal images, human embryonic stem cells are identified with a pluripotency marker (NANOG, in green). DNA methylation (red) is reduced in reset cells. [Wolf Reik and Gabriella Ficz, Babraham Institute]

  • Adult human stem cells are routinely taken back to early developmental states—but not all the way back, not to the very cusp of human development. Yes, under the ministrations of scientists, these cells are typically induced to pluripotency, the ability to follow different developmental courses. Yet these cells are not blank slates. They are not “pristine.” They retain biases toward particular cell fates and tissue types, complicating their use in therapeutic applications, such as regenerative medicine.

    “Almost zero” stem cells naturally vary. Their developmental clocks are not quite in synch, and their developmental biases differ in strength. 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 considerably 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 (7–9 days old).

    The scientists achieved for human cells a feat previously limited 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 naïve pluripotency, human cells do not.

    To overcome this difficulty, the researchers took a new approach. They used reprogramming methods to express two different genes, NANOG and KLF2. These genes, which needed to be expressed but briefly, caused the network of genes that controls the cell to “reboot” and induce the naïve pluripotent state.

    This finding appeared September 11 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 signaling, are phenotypically stable, and are karyotypically intact,” wrote the authors. “They differentiate in vitro and form teratomas in vivo. 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 lines.”

    The reset human stem cells showed a loss of methylation marks 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 unrestricted 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 Professor 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 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 specialized cell types for regenerative tissue grafts.

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