Induced Stem Cells Made Directly in Mice
By Anette Breindl
Since their initial description in 2007, induced pluripotent stem (iPS) cells have been investigated as a possible alternative to embryonic stem cells. By adding a cocktail of so-called reprogramming factors, scientists can turn mature cells – most often skin cells – into pluripotent cells that can turn into many different cell types.
So far, iPS cells have been made in cell culture, with the goal of first making iPS cells from skin cells, differentiating them into the desired cell type, and using them for research or transplanting them back into patients. But this week, researchers described transforming mature cells into iPS cells directly in animals, using a genetic vector to deliver the reprogramming factors into specific cell types.
“It is possible to generate pluripotent stem cells directly within tissue in living organisms,” senior author Manuel Serrano told reporters at a press conference announcing the findings. “Up to now, this has been done only in vitro.”
Moreover, co-author Maria Abad told reporters, the iPS cells created by this method are “of even better quality than those produced in the lab.” And “this increased plasticity could hold the key for further advances” in using the cells.
“We think that this opens new possibilities in regenerative medicine,” Serrano said of the work, which was published in the Sept. 12, 2013, issue of Nature.
In their experiments, Abad, Serrano and their colleagues, who are at the Spanish National Cancer Research Center, engineered mice to express the same four transcription factors that were originally used by Shinya Yamanaka and his colleagues in the first work on iPS cells. (See BioWorld Today, Nov. 21 , 2007.)
So far, to be fair, the expression of the transgenes is mainly a surefire way to rapidly kill the mice, because they rapidly develop multiple teratomas – tumors that originate from stem cells and contain more than one tissue type.
But although such teratomas are in one sense too much of a good thing, they showed that in principle, many different cell types in many organs could be transformed in vivo. Serrano said that the approach could potentially be used for cells including heart cells, pancreatic beta cells and neural cells for the treatment of spinal cord damage, although he was skeptical that the approach could work for neurodegenerative disorders.
Moreover, in two mice, the authors saw the development of embryo-like structures that contained cells derived from all three layers of the germ line as well as cells that appeared to be placenta-like. No one has managed to generate placental cells from either iPS or embryonic stem cells, and so the team concluded that its cells are not just pluripotent, that is, can generate multiple cell types, but that they may have the potential for totipotency – the ability to generate every cell type in the body that is usually the privilege of the zygote and its descendants for the first few cell divisions.
At this point, the work is proof of principle only that iPS cells can be created directly in animals – not even proof of principle that such cells would help in the regeneration of damaged tissue. Even if that turns out to be the case, clinical use will depend on success in finding a “middle ground” in their capacities, Serrano said, since no one wants to get gene therapy that has them growing embryo-like structures.
“We have to find conditions that are not sufficient [for] full reprogramming but that are sufficient to improve regeneration.” Such reprogramming would then be delivered locally using targeted gene therapy vectors, and controlled using an on-off switch, though whether that switch would be the same as used in the mice is still unclear.
If it works, Abad, Serrano and their colleagues said their approach has two advantages over generating stem cells in culture.
First, it doesn’t require in vitro manipulation of the cells. Second, such cells do not need to be transplanted, which might make it possible to avoid one of the current stumbling blocks of harnessing stem cells clinically: engraftment.
Engraftment is “the main obstacle” with in vitro-produced iPS cells, Serrano said.
“In general, this engraftment doesn’t work, or it works very inefficiently. . . . There are very few examples of efficient engraftment of such cells,” he noted.
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