Scientists break stem cell barrier
12 Sep 2014
Human stem cells have been reset to their earliest developmental state in the lab, according to new research.
A team of researchers led by the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute at the University of Cambridge has successfully ’reset’ human pluripotent stem cells to the earliest developmental state - equivalent to cells found in an embryo before it implants in the womb (7-9 days old).
These pluripotent stem cells are considered truly ’pristine’ as they have the potential to differentiate into almost all cell types in the body, and mark the true starting point for human development, researchers said.
It’s as if the developmental clock has not stopped at the same time and some cells are a few minutes ahead of others
MRC professor Austin Smith
According to researchers, the discovery, which was published yesterday in the journal Cell, will lead to a better understanding of human development and could allow the production of ’safe and more reproducible starting materials’ for a wide range of applications including cell therapies.
Prior to this breakthrough, such early state stem cells have been impossible to replicate in the laboratory.
To combat this, researchers induced a ’ground state’ by rewiring the genetic circuitry in human embryonic and induced pluripotent stem cells.
The researchers said their reset cells exhibit many of the characteristics of authentic pristine 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,” said MRC professor 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 said the process of generating stem cells in the lab is easier to control in mouse cells, which can be frozen in a state of naïve pluripotency using a protein called LIF.
Unfortunately, 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.
To overcome this issue, researchers introduced two genes - NANOG and KLF2 - causing the network of genes that control the cell to reboot and induce the naïve pluripotent state.
These introduced genes need only be present for a short period of time; thereafter reset cells can self-renew indefinitely to produce large numbers of other cell types, including nerve and heart cells.
According to researchers, the naïve state of the reset stem cells may 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 specialised 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 said.
“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.”
