Posted on November 5, 2015 at 11:45 PM
There is considerable enthusiasm for the use of “reprogrammed” pluripotent stem cells, or iPSCs, for use in the laboratory and as possible cellular treatment for people with certain injuries or diseases. This enthusiasm is warranted; human iPSCs (hiPSCs) are readily obtained, and without the destruction of a human embryo as is needed to obtain a “natural” human embryonic stem cell (hESC). Therefore, iPSCs are often described as the “ethical” stem cells.
Just how dissimilar iPSCs may be to “natural” ESCs has been controversial, however. A recent publication in the journal Nature Biotechnology strongly suggests that while not identical, it may well be that they can be treated interchangeably in the lab or for possible clinical use.
In the paper (journal subscription or $32 online article purchase required), scientists from Harvard, MIT, Johns Hopkins, and other major research institutes in the U.S. and Italy describe an elegant experiment. They took two previously established hESCs—derived from two different human embryos, to be sure—and let them differentiate into a specific type of adult cell called a fibroblast. Then they took the fibroblasts and reprogrammed them into hiPSCs using a technique that avoids the risk of making the cells malignant—a risk associated with some other reprogramming methods. To put it another way, they let the hESCs mature and then “back-translated” them, as it were, to a pluripotent state with the reprogramming step. (Recall that a “pluripotent” cell is capable of becoming many different adult cell types.) They did the appropriate experimental controls.
They looked specifically at whether the expression—or transcription into messenger RNA—of the hESCs and the hiPSCs differed. And the answer was yes, but not very much—only 49 genes, they counted, out of a total of about 30,000 in the genome, when they compared the hiPSCs with the hESC (the one of the two cell lines) it originally came from. There were greater differences between hiPSCs that came from one of the two hESCs, and the other hESC. Gene modifications called “epigenetic” changes, that turn genes on or off, were also so similar as to be virtually identical.
The scientists also tested the function of a couple of the differentially-expressed genes, and found no difference between the hESC and its corresponding hiPSCs.
So what matters most is the “genetic background”—that is, the genes of the individual from whom an hiPSC is derived—in determining what that hiPSC looks like, in terms of its genes and function. They suggest that earlier reports of big differences between iPSCs and ESCs could be explained by a sort of “apples to oranges” comparison across different types of cells.
The big implication is that, for most studies or applications, it would not matter whether hESCs—requiring destruction of an embryo—or hiPSCs were used, provided that the pedigree of the latter were known well enough. This would in turn provide comfort to developers of treatments with reprogrammed stem cells that they would not be more likely to succeed if they used the “natural” ESCs. The differences seem unlikely to matter.
This work comes from a well-pedigreed group, but I’d still like to see it reproduced and confirmed. There have just been too many retractions in high-profile science in recent years, because of mistakes or even fraud. There are other issues, too: It’s not clear whether the two cell types would be equivalent if transplanted into an individual other than the one from whom they were derived. The work was done with male cells, and female cells, with two X chromosomes, could well behave differently. I wonder whether, because the hESCs they started with were cell lines that had already been established and preserved for lab use, the act of preservation might not have changed them from their original state in ways that are not fully appreciated. This seems unlikely, but possible.
Recall also that future experiments to confirm this work would necessarily have to use hESCs initially derived from the destruction of embryos. The use of previously-established lines limits this ethical concern a bit, I imagine, but it is possible that future hESCs would be obtained from future embryos.
Recall also that iPSCs are not free of special ethical concerns (that is, beyond the usual principles governing clinical trials, for example): if iPSCs were allowed to differentiate into germ cells (sperm or eggs) that could then be used to create a new embryo, at least some of the reproductive ethics concerns that accompany cloning could well apply.
But overall, score one for reprogrammed stem cells.