Monthly Archives: September 2014

Researchers at EMBL-EBI have resolved a long-standing challenge in stem cell biology by successfully 'resetting' human pluripotent stem cells to a fully pristine state, at point of their greatest developmental potential. The study, published in Cell, involved scientists from the UK, Germany and Japan and was led jointly by EMBL-EBI and the University of Cambridge.

Embryonic stem (ES) cells, which originate in early development, are capable of differentiating into any type of cell. Until now, scientists have only been able to revert 'adult' human cells (for example, liver, lung or skin) into pluripotent stem cells with slightly different properties that predispose them to becoming cells of certain types. Authentic ES cells have only been derived from mice and rats.

"Reverting mouse cells to a completely 'blank slate' has become routine, but generating equivalent nave human cell lines has proven far more challenging," says Dr Paul Bertone, Research Group Leader at EMBL-EBI and a senior author on the study. "Human pluripotent cells resemble a cell type that appears slightly later in mammalian development, after the embryo has implanted in the uterus."

At this point, subtle changes in gene expression begin to influence the cells, which are then considered 'primed' towards a particular lineage. Although pluripotent human cells can be cultured from in vitro fertilised (IVF) embryos, until now there have been no human cells comparable to those obtained from the mouse.

Wiping cell memory

"For years, it was thought that we could be missing the developmental window when nave human cells could be captured, or that the right growth conditions hadn't been found," Paul explains. "But with the advent of iPS cell technologies, it should have been possible to drive specialised human cells back to an earlier state, regardless of their origin -- if that state existed in primates."

Taking a new approach, the scientists used reprogramming methods to express two different genes, NANOG and KLF2, which reset the cells. They then maintained the cells indefinitely by inhibiting specific biological pathways. The resulting cells are capable of differentiating into any adult cell type, and are genetically normal.

The experimental work was conducted hand-in-hand with computational analysis.

"We needed to understand where these cells lie in the spectrum of the human and mouse pluripotent cells that have already been produced," explains Paul. "We worked with the EMBL Genomics Core Facility to produce comprehensive transcriptional data for all the conditions we explored. We could then compare reset human cells to genuine mouse ES cells, and indeed we found they shared many similarities."

Together with Professor Wolf Reik at the Babraham Institute, the researchers also showed that DNA methylation (biochemical marks that influence gene expression) was erased over much of the genome, indicating that reset cells are not restricted in the cell types they can produce. In this more permissive state, the cells no longer retain the memory of their previous lineages and revert to a blank slate with unrestricted potential to become any adult cell.

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Scientists revert human stem cells to pristine state

A new type of human stem cell, never seen in nature, has been made in the lab. The cells may be the primordial embryonic cell from which all our cells are created. They should be better at making replacement organs than existing stem cells.

"We see it as a blank canvas, the starting point for all tissues in the body," says Austin Smith of the University of Cambridge, who led the team that developed the cells.

It is a big claim, and the stem cell field has been rocked by false ones in recent times. Supposedly revolutionary procedures have turned out to be flawed, most recently the claim in Nature earlier this year that adult cells could be turned into stem cells simply by exposing them to acid. Science and Cell rejected the "STAP cells" papers, but Nature accepted them only to be forced to retract them in July.

However, Smith's findings are getting cautious support. "There are great people contributing to this paper, and their reputations are on the line," says Chris Mason of University College London. "I would be really surprised if it's not the real deal."

In theory stem cells can develop into any kind of cell, so they could be used to repair damaged organs or even build them from scratch. But most stem cells aren't that flexible. The best ones are "pluripotent", meaning they can turn into anything. Such cells have to be taken from embryos, which is controversial, or made by reverting adult cells to their embryonic state, called induced pluripotent stem cells.

But these pluripotent stem cells still carry genetic baggage from their previous existence. For instance, genes may have been activated for a particular course of development into a kidney, say or turned off by a chemical marking process called methylation.

"This [baggage] has been one of the confounding problems in this area," says Smith. The cells aren't completely neutral about what they develop into, and they are all different so can't be standardised.

The new cells have had their cellular memories wiped clean. Their genes have been cleansed of most methylation markers, so they behave more predictably and transform more consistently into other tissues. The team hopes that this will make them a better building block for organs and tissues than existing embryonic stem cells.

"Nothing has been written or drawn on them to tell them what to do or become," says Smith. "These cells could be a better and more pristine starting point."

Called naive stem cells, these have long been known in mice and rats, but they have never been found in humans.

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Ultimate human stem cells created in the lab

London, Sept 14:

Scientists have created a new type of human stem cell in the lab which they believe will be better at making replacement organs than existing stem cells.

In theory stem cells can develop into any kind of cell, so they could be used to repair damaged organs or even build them from scratch. But most stem cells are not that flexible, researchers said.

The best ones are pluripotent, meaning they can turn into anything. Such cells have to be taken from embryos or made by reverting adult cells to their embryonic state, called induced pluripotent stem cells, New Scientist reported.

But these pluripotent stem cells still carry genetic baggage from their previous existence. This ([baggage) has been one of the confounding problems in this area, said Austin Smith of the University of Cambridge, who led the team that developed the new cells.

The new cells have had their cellular memories wiped clean. Their genes have been cleansed of most methylation markers, so they behave more predictably and transform more consistently into other tissues.

The team hopes that this will make them a better building block for organs and tissues than existing embryonic stem cells.

Nothing has been written or drawn on them to tell them what to do or become. These cells could be a better and more pristine starting point, said Smith.

Called naive stem cells, these have long been known in mice and rats, but they have never been found in humans.

To make them, Smith and his colleagues mimicked the process that creates their mouse counterparts. They gave human embryonic stem cells extra copies of two genes, Nanog and Klf2, which triggered the gene network needed to make the naive cells.

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New type of human stem cell created in lab