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US, UK Scientists Derive First-Ever Rat ESCs To Allow Better Human Disease Models

In two separate studies published last week in Cell, researchers at the University of Southern California and the University of Cambridge in the UK claimed that they have, for the first time, derived authentic embryonic stem cells from rats.
This finding will allow scientists to create more effective animal models than the mouse models currently available for the study of many human diseases, the researchers said.
The publication of these papers marks a milestone for UK-based Stem Cell Sciences, which has licensed the underlying technology for both studies from Edinburgh University, and plans to commercialize the rat ESCs. Last September, SCS announced that “two independent laboratories,” one in the US and one in the UK, had successfully achieved germ-line transmission from rat ESCs using technologies licensed to SCS by Edinburgh University, and developed by Austin Smith and his group, who are now at Cambridge (see CBA News, 9/5/08).
SCS said at the time that it plans to engage in confidential discussions with interested parties seeking a sublicense to use rat ESCs in their commercial drug discovery programs.
Under the terms of its agreement with Edinburgh University, SCS has exclusive rights to commercialize the rat ESCs, the specific medium used to generate and grow the cells, and the rats derived therefrom.
In an e-mail to CBA News this week, Alastair Riddell, CEO of Stem Cell Sciences, said, “We will be focusing more on the utility of this technology in creating animal models for drug discovery than for cell-based reagents for assays.”
Qi-Long Ying, an assistant professor of cell and neurobiology at the Keck School of Medicine at USC and the principal investigator on the current USC study, said that the next step would be to generate a gene-knockout rat as a proof of principle. He explained that the animal would be created by knocking out the hypoxanthine phosphoribosyl transferase-encoding gene.
Until now, authentic ES cells have never been established from animals other than mice. This new understanding into how ESCs are maintained in culture may also allow scientists to establish real ESC lines from a number of other mammals, which could have significant implications for the development of drug therapies, Ying said.
Mouse ESCs have been available for more than 27 years. “Mouse ESCs are very powerful, because we can make genetic modifications in the ESCs and then generate animals using these genetically modified ESCs,” said Ying.

“We applied these three inhibitor conditions to the derivation of rat ESCs. The first time we tried it, we were successful.”

But researchers have been eager to apply the same approach to rats because they are more physiologically similar to humans than mice. “We can create a lot of models in rats that are very similar to humans, but we cannot do this in mice. For example, we can create a model of hypertension, neurological diseases, and a lot of cancers, in rats,” Ying said.
In addition, rats are approximately ten times bigger than mice. This makes it easier to perform medical procedures often used with humans, such as blood draws. 
To date, however, attempts to establish ESCs from the rat have failed because the conditions used to derive mouse ESCs did not work for rat ESC derivation. But earlier this year, Ying and his colleagues discovered a mechanism underlying mouse ESC self-renewal that ultimately enabled the rat cell breakthrough.
In a paper published in Nature in May, Ying and his group described that they could maintain mouse ESCs in the presence of three small molecules that specifically inhibit glycogen synthase kinase 3 (GSK3), mitogen-activated protein kinase kinase (MEK), and fibroblast growth factor receptor (FGFR) tyrosine kinase.
They also found that, contrary to popular belief, mouse ESC self-renewal did not require activating signals from the leukemia inhibitory factor/STAT3 and the bone morphogenic protein/SMAD pathways, but only needed to be protected from inductive differentiation cues.  
“We applied these three inhibitor conditions to the derivation of rat ESCs. The first time we tried it, we were successful,” said Ying.
The researchers proved that these rat ESCs express pluripotency markers, and retain the capacity to differentiate into derivatives of all three germ layers. However, most importantly, “we have proved that these ESCs can contribute to the formation of a chimeric rat, and can be transmitted to the next generation,” Ying said.
In their paper, the investigators from the University of Cambridge used similar three inhibitor, or “3i,” conditions to derive rate ESCs. They also demonstrated that two-inhibitor conditions, using an MEK and a GSK3 inhibitor, enabled the derivation of rat ES cell lines with the authentic properties of authentic ESCs: long-term self-renewal, pluripotency, teratoma formation, the ability to incorporate into the developing embryo, colonization of the germline, and generation of functional gametes.
Smith, corresponding author on the University of Cambridge study, did not respond to a request for comment in time for deadline.
“These studies constitute an impressive milestone, springing from the earlier discovery by Ying and Smith of the critical importance of shielding the so-called "pluripotent ground state" of presumptive ESCs from encounters with differentiation pathway triggers,” Thoru Pederson, a professor of biochemistry and molecular pharmacology at the University of Massachusetts Medical School, told CBA News this week in an e-mail. 
He added that the advantages of rat ESCs over mouse in terms of human drug screening and modeling pathophysiology suggests a “considerable commercial potential of rat ESCs, assuming that their novel features pass the tests of non-obviousness and utility that will be keys to patentability.”
Pederson also said that this recent work opens to door to learning a great deal about embryonic development and cell differentiation in a mammal in which such investigation has lagged behind that in the mouse.
The current mouse ESC market is comprised primarily of the culture medium and other reagents. “I am not sure about the rat ESC market, but I was told that it could be a huge market if we can generate disease models using rat ESC-based technologies,” he said.
SCS previously estimated that the market for this technology would be worth more than $80 million per year worldwide.

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