Induced Pluripotent Stem Cell Setback?

Last week, Nature reported a new study which found that a promising new type of stem cell might be rejected by a patient's immune system. Back in 2006, researchers managed to create induced pluripotent stem (iPS) cells using adult cells. As the New York Times explains:

The initial creation of human iPS cells in 2007 electrified scientists because the cells seemed to have two big advantages over embryonic stem cells. They were not controversial, because their creation did not entail the destruction of human embryos. And since the stem cells could be made from a particular patient's skin cells, they could be used to make tissues that presumably would not be rejected by that patient's immune system.

But that latter assumption was never really tested, until now. When Yang Xu, a biologist at the University of California, San Diego, and colleagues did so, they found that iPS cells made from mouse skin cells were nonetheless rejected by genetically identical mice.

The new research tried installing iPS cells in mice where they were rejected. The researchers speculate that the process of switching adult cells into iPS cells abnormally activates some genes producing proteins that the immune system interprets as being foreign. Will this failure lead back to the process of producing cloned embryos from which patient-specific therapeutic stem cells suitable for transplant can be derived? Earlier studies showed that tissues made from such cloned embryonic stem cells are not rejected.

Perhaps not. Researchers have been developed a new method using microRNA to transform adult cells into stem cells far more efficiently. It is yet unknown if these cells would be deemed abnormal by a patient's immune system. In addition, last week the New England Journal of Medicine published work in which researchers identified adult stem cells in the lungs. These cells have the power to differentiate into various tissues and might be used to repair a patient's damaged lungs without being rejected.

Comments

[squarooticus]

I wonder if researchers will figure out something new about autoimmune conditions from this?

[House]

It's not Lupus.

[Fist of Etiquette]

..the immune system interprets as being foreign.

OMG, do I have to think of everything? Irradiate the patient and destroy his immune system first. Duh.

[PIRS]

I am no biologist (nor do I play one on TV) but I wonder if anyone has done research into creating a quasi-synthetic "neutral" DNA that could be used in everybody (or nearly so)? Does anybody know if this would even be possible? Something like sythetic blood that would not be rejected by anyone regardless of blood type or RNA etc. etc. ?

[Metazoan]

I don't think that makes a whole lot of sense, no offense. DNA isn't usually what's rejected by the immune system. Often it's a protein antigen, and I think often the modifications to the protein can irritate the immune system. Bacterial cell membrane components can also do that deed. But not usually DNA.

[JD]

There has been work done on making proteins that are less likely to be rejected by the immune system.

The example I'm most familiar with is engineering Factor VIII (the protein missing in the most common form of hemophilia) so that the recombinant protein given to patients is less likely to be rejected by the immune system, while still maintaining its ability to participate in the clotting cascade.

[rogue biologist]

heh, trying to glycosylate or pegylate the shit out of it, eh? Good damn luck...

[rather]

The researchers speculate that the process of switching adult cells into iPS cells abnormally activates some genes producing proteins that the immune system interprets as being foreign

I think there are other possibilities too. Just because the embryonic cells were not rejected does not prove that it is the adult stem cells themselves but perhaps a unknown in either. This makes me think of the tumor's that sometimes grow teeth and hair.

[JD]

They don't just speculate that it might be production of immunogenic proteins.

In the paper, the authors identify a number of proteins that are expressed in iPS cells but not in ES cells. Some of these proteins have already been implicated in immune responses to tumors.

When they expressed the identified proteins in embryonic stem cells, the cells were rejected by the immune system.

[rogue biologist]

uhm, if you read the article CAREFULLY, it's implantation of iPS itself that causes immune rejection. Presumably, a real treatment would involve implantation of differentiated cells, not pluripotent ones.

Finally, when scientists do molecular biology, they often implant foreign selective markers to make sure that the change they make to the DNA is there (eg neo gene conferring gentimycin resistance). This could be responsible, would not surprise me if the scientists were not careful to remove the gene post modification.

[A.G. Pym]

@PIRS - it's not DNA or RNA that creates rejection or allergic reactions. It's the proteins coded by those templates that exist on the surfaces tested by any individual's immune cells.

[rather]

A.G. Pym, your site has a virus

[rogue biologist]

Depends. In lupus, there seem to be antibodies to dsDNA.

But, of course, in this case, it's not lupus.

[rather]

what is it with you and lupus? A groundhog day meme?

[JD]

Researchers have been developed a new method using microRNA to transform adult cells into stem cells far more efficiently. It is yet unknown if these cells would be deemed abnormal by a patient's immune system.

I'd be willing to bet they would be rejected as well. The Nature paper in question used two different methods to create iPS cells, and cells created by both methods were rejects (albeit at different frequencies). It's likely that a third method (or more--there are probably close to a dozen published methods of making iPS cells) would have the same problem.

[rogue biologist]

Instead of rushing to assumptions, how about considering that the method that overexpressed cancer markers had the higher degree of rejection. Seeing as how the immune system is responsible to a degree for staving off cancer, how about - uhm, making iPSes with less cancer?

[Irv Arons]

There's more to this story, as I've just published online.

Please note the comments in the last two paragraphs of my introduction:

Stem Cells in Ophthalmology Update 7: Research Studies with Induced Pluripotent Stem Cells Suggest Opposite Results

Two research studies were published this week, about the use of induced pluripotent stem cells (iPSCs) in treating retinal problems, but with opposing results.

In one study, published in Nature, Dr.Yang Xu and his colleagues at the University of California, San Diego, found that iPSCs made from mouse skin cells were rejected by genetically identical mice. This study was just published in Nature. (Similar studies with iPSCs, also published in Nature earlier this year, also showed problems, including genetic and epigenectic abnormalities. See Stem Cells in Ophthalmology Update 5: Gene Defects Common in Induced Stem Cells.)

In the second study, Dr. Budd Tucker and his colleagues at the Schepens Eye Research Institute used iPSCs derived from skin to regenerate large areas of damaged retinas and improve visual function in specially grown degenerative mice. This study was just published in PloS ONE.

The difference may be in the way the stem cells were used in the experiments. In the first case, the iPSCs (along with embryonic stem cells (hESCs)) were directly introduced into the mice of the same strain from which they were created and the implanted iPSCs encountered an immune response, but not the implanted hESCs. In the Schepens study, the harvested iPSCs were forced to express transcription factors, and with additional chemical coaxing, developed into precursors of retinal cells. These latter cells were introduced into the mouse model eyes with retina degenerative disease. Within four to six weeks, the researchers observed that the transplanted cells had taken up residence in the appropriate retinal area (the photoreceptor layer) and had begun to integrate and assemble into healthy looking retinal tissue.

Another difference, as pointed out to me by an expert in the field in a private communication, is the extreme difference in transplant sites between the two studies. The eye, used in the Schepen's study, is considered an immune privileged body, whereas the flank, where the teratomas were formed in the UC-SD study, is highly immunogenic. As for the immune rejection seen in the Nature paper it was far from complete, i.e., see the specific details of teratoma formation percentages. Nevertheless, the true importance of the Nature paper comes from the fact that everyone in the field just assumed that iPSCs would be unseen by the immune system, and that was not the case.

Here's the link to my report: http://tinyurl.com/ophthstemcells-update7

Regards,
Irv Arons

[rather]

so interesting

[rogue biologist]

1) blogwhore
2) "private communication" = means, "you're a retard". I'm a biophysicist and even I knew that the eye is immunoprivledged

[rather]

biophysicist? You sound more like epi's welcome committee

[MysteryFish]

I give you points for putting the article abstracts in your blog post,as well as links to the actual studies, which means it somewhat contains useful information.

Unlike rather's blog, which is like someone vomiting into your eyes. Given their immunoprivileged status, this will likely cause an infection.

However, given the special nature of the eye with regards to the transplant of foreign tissue - as you yourself acknowledge in your last paragraph - I'm curious as to how you reached the conclusion that the studies suggested opposite results.

[rather]

Unlike rather's blog, which is like someone vomiting into your eyes

Your insults feed me coward

[rather]

hey that was a sockpuppet

[rather]

FY, and stop using my handle shithead