Cambridge scientists have successfully reset human pluripotent stem cells to the earliest developmental state equivalent to cells found in an 7-9 day old embryo before it implants in the womb.

The researchers believe that these pristine stem cells, which have until now been impossible to replicate in the lab, could mark the true starting point for human development.

It is hoped that the discovery, published in Cell, will lead to a better understanding of human development and could in future allow the production of safe and more reproducible starting materials for a wide range of applications including cell therapies.

Researchers led by the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute at the University of Cambridge, have 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 nave embryonic stem cells isolated from mice, suggesting that they represent the earliest stage of development.

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.

To date, scientists have struggled to generate human pluripotent stem cells that are truly pristine 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 theyre not a truly blank slate. This may explain why existing human pluripotent stem cell lines often exhibit a bias towards producing certain tissue types in the laboratory.

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 Professor Austin Smith, Director of the Stem Cell Institute, who co-authored 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. Its as if the developmental clock has not stopped at the same time and some cells are a few minutes ahead of others.

The process of generating stem cells in the lab is easier to control in mouse cells, which can be frozen in a state of nave pluripotency using a protein called LIF. Human cells are not as responsive to LIF, so they must be controlled in a different way that involves switching key genes on and off. For this reason scientists have been unable to generate human pluripotent cells that are as primitive or as consistent as mouse embryonic stem cells.

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 nave 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.

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Stem cell advance made by Cambridge scientists