Hitting the stem cell ‘reset’

Scientists return human stem cells to earliest developmental state

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CAMBRIDGE, U.K.—Scientists have managed to “reset” human pluripotent stem cells to their earliest developmental state, equivalent to cells found in an embryo before it implants in the womb (seven to nine days old). These “pristine” cells could be the true starting point for human development, but have until now been impossible to recreate in the lab.
The findings, published in Cell, are expected to lead to a better understanding of human development and could eventually enable the production of safe and more reproducible starting materials for a wide range of applications including cell therapies.
In the journal article, authors Dr. Yasuhiro Takashima, Prof. Austin Smith, et. al., note that, “Our findings suggest that authentic ground-state pluripotent stem cells may be attainable in human, lending support to the notion of a generic naive state of pluripotency in mammals. In human, the naive-state transcription factor circuitry appears in large part to be conserved but requires greater reinforcement to be stably propagated. Disposition to collapse reflects the transient nature of naive pluripotency in the embryo (Nichols and Smith, 2009). The imperative for developmental progression may be intrinsically stronger in primates that, unlike rodents, have not evolved the facility for embryonic diapause (Nichols and Smith, 2012).”
In conclusion, the authors state that, “Human genetic variation notwithstanding, epigenome status may influence consistency of both undifferentiated phenotype and differentiation behavior. Low genomic H3K9me3 and genome-wide DNA hypomethylation point to epigenome erasure in reset cells, as in early embryos. It will be of great interest to determine the precise functional impact of such epigenetic cleansing.”
Human pluripotent stem cells, which have the potential to become any of the cells and tissues in the body, can be made in the lab either from cells extracted from a very early-stage embryo or from adult cells that have been induced into a pluripotent state.
However, scientists have struggled to generate human pluripotent stem cells that are truly pristine (or naive). Instead, researchers have only been able to derive cells which have advanced slightly further down the developmental pathway. These bear some of the early hallmarks of differentiation into distinct cell types—they’re not a truly “blank slate.” This may explain why existing human pluripotent stem cell lines often exhibit a bias toward producing certain tissue types in the laboratory.
In this latest work, the team led by the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute at the University of Cambridge has managed to induce a ground state by rewiring the genetic circuitry in human embryonic and induced pluripotent stem cells. Their “reset cells” share many of the characteristics of authentic naive embryonic stem cells isolated from mice, suggesting that they represent the earliest stage of development.
“Capturing embryonic stem cells is like stopping the developmental clock at the precise moment before they begin to turn into distinct cells and tissues,” explains MRC Prof. Austin Smith, co-author of the paper. “Scientists have perfected a reliable way of doing this with mouse cells, but human cells have proved more difficult to arrest and show subtle differences between the individual cells. It’s as if the developmental clock has not stopped at the same time and some cells are a few minutes ahead of others.”
The researchers overcame this problem by introducing two genes—NANOG and KLF2—causing the network of genes that control the cell to reboot and induce the naive pluripotent state. Importantly, the introduced genes only need to be present for a short time. Then, like other stem cells, reset cells can self-renew indefinitely to produce large numbers, are stable and can differentiate into other cell types, including nerve and heart cells.
By studying the reset cells, scientists will be able to learn more about how normal embryo development progresses and also how it can go wrong, leading to miscarriage and developmental disorders. The naive state of the reset stem cells may also make it easier and more reliable to grow and manipulate them in the laboratory and may allow them to serve as a blank canvas for creating specialized cells and tissues for use in regenerative medicine.
“Our findings suggest that it is possible to rewind the clock to achieve true ground state pluripotency in human cells,” Smith adds. “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.”
Dr. Rob Buckle, head of regenerative medicine at the MRC, added: “Achieving a true ground state in human pluripotent stem cells is seen as a significant milestone in regenerative medicine. With further refinement, this method for creating ‘blank’ pluripotent cells could provide a more reliable and renewable raw material for a range of cellular therapies, diagnostics and drug safety screening tools. This is likely to be a highly attractive prospect to industry and regulators.”
The paper published in Cell is entitled “Resetting transcription factor control circuitry towards ground state pluripotency in human.”

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