Researchers have successfully “reset” human stem cells back to their earliest pristine state, when they’re at their greatest developmental potential. The reset cells may also represent the starting point for the formation of tissues in human embryos, giving researchers the ability to study early development like never before. The work was published in Cell this week.
Embryonic stem cells originate early in development, and they're capable of differentiating into any type of cell (called pluripotency). Researchers have only been able to revert adult cells, usually from skin, into what’s called induced pluripotent stem (iPS) cells. True embryonic stem cells have only been derived from rodents.
“Reverting mouse cells to a completely ‘blank slate’ has become routine, but generating equivalent naïve human cell lines has proven far more challenging,” says Paul Bertone of the European Bioinformatics Institute in a news release. “Human pluripotent cells resemble a cell type that appears slightly later in mammalian development, after the embryo has implanted in the uterus.” But by then, subtle changes in the expression of genes have already begun to influence the cells, priming them to become cells of certain lineages.
So Bertone, Austin Smith from University of Cambridge, and colleagues introduced two different genes—NANOG and KLF2—that ignited a network of various elements that reset the cells. They then maintained the cells indefinitely by inhibiting specific biological pathways. The resulting ground-state cells are capable of differentiating into any adult cell type. And they’re genetically normal.
The team showed that biochemical marks influencing gene expression (the result of a modification process called DNA methylation) were erased in numerous places along the genome (pictured above). That suggests that the reset cells aren’t restricted to what cell types they can become. In this more permissive state, the cells have been wiped clean of the memories of their previous cell lineages—they’ve essentially become blank slates.
“For years, it was thought that we could be missing the developmental window when naïve human cells could be captured,” Bertone explains. “But with the advent of iPS cell technologies, it should have been possible to drive specialized human cells back to an earlier state, regardless of their origin—if that state existed in primates.”
Smith adds: “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.” By resetting stem cells, researchers also hope that the base-state cells received by patients of regenerative therapies can develop into the correct type the patient needs, like replacement nerve or heart cells.
Images: Babraham Institute (top), EMBL-EBI (middle)
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