As a feast to the minds of stem cell researchers the recipe formulated for capturing authentic embryonic stem cells from mice is found to be applicable in rats other mammals including cows, pigs and even humans.
The new discovery made in labs at both the University of Edinburgh and the University of Southern California (USC), Los Angeles, as a result of two studies, is a major breakthrough for biomedical research, said Qi-Long Ying, an author on both studies.
It will allow researchers to readily produce genetically altered strains of rats, with conditions that mimic human disease, in a very targeted way.
Austin Smith led the research team at the University of Edinburgh and Ying led the USC team.
The researchers said that humans and rats are physiologically more similar than humans and mice, making the study of rats more directly applicable to people, and rats' larger size also makes them easier to work with in many cases. Humans and rats also tend to have similar responses to drugs.
The results provided evidence to the notion that embryonic stem cells will remain in their undifferentiated, pluripotent state when they are shielded from particular outside signals. Pluripotent refers to the ability to differentiate into any cell or tissue type.
Embryonic stem cells are derived from the inner cell mass of blastocysts, which are hollow balls of cells that form in early development. The inner cell mass is a cluster of cells inside the blastocyst that goes on to form the embryo.
Authentic embryonic stem cells are defined by three cardinal properties: unlimited symmetrical self-renewal in the lab; comprehensive contribution to primary chimeras; and generation of functional egg and sperm for genome transmission.
Chimeras are produced when embryonic stem cells are inserted into a developing blastocyst and those stem cells go on to contribute to a normal embryo with cells of two origins, Ying explained.
As embryonic stem cells can contribute to the germ line, any genetic alterations they carry, like the loss or gain of a gene, can be passed on to the next generation.
While embryonic stem cells have been routinely derived from particular strains of mice since 1981, their capture from rats or other animals had remained elusive.
Now, the researchers have shown that a two- or three-ingredient concoction known as 2i or 3i respectively, which inhibits signals that would otherwise activate the differentiation process, maintains rat embryonic stem cells in their natural default state, allowing them to self-renew, or multiply, as generic stem cells. (The cocktails include inhibitors of GSK3, MEK, and FGF receptor tyrosine kinases.)
Significantly, the isolated cells can produce high rates of chimerism when reintroduced into early stage embryos and can transmit through the germline, they report.
"In the past two decades, embryonic stem cells have been routinely used to create loss of function (knockout) or gene replacement (knockin) mutations by homologous recombination in the mouse, providing an invaluable tool for the functional characterization of genes. Now, the availability of true rat embryonic stem cells provides an opportunity to adapt the technology developed in the mouse to the rat," wrote Ying's group.
The two studies are published the recent issue of the journal Cell, a Cell Press publication.