Immunogenicity of iPS cells

On the matter of the induced pluripotent stem cells (iPSCs) those of us in the stem cell research community are like babies who have met a large body of water; pool, ocean; for the first time. We want to jump in and play, but we also have some doubts.

iPSCs hold great potential. Like the embryonic stem cells (ESCs) they can become any cell in the body. Unlike ESCs, they are fairly easy to make and come with less ethical problems. ESCs can only be isolated from a very young embryo. iPSCs on the other hand are created through the manipulation of adult cells. A skin biopsy or blood sample can provide the starting material.

The hope is, once we learn more about these cells and how they differentiate, we can make patient specific iPSCs and provide the cells or organs required. A new heart, a new lung, muscle cells etc (PBSs Nova has a wonderful documentary on the subject). This technology kills two birds with one stone. First, no more organ transplant waiting lists. Organs can be made in the lab when needed. Second, no immunosuppression. In the current transplant protocols, the immune system of the patient is suppressed, because no donor is a perfect match and thus the transplanted organ is a stranger and a target for the immune system. An organ made from the iPSCs on the other hand is a perfect match and it will not trigger a response.

Or so we thought.

There has been a flurry of papers recently comparing the two types of pluripotent cells, the new technology, iPSCs and the gold standard, ESCs. Again and again the conclusion has been that iPSCs are a good replica, but there are differences. Dr. Yang Xu and colleagues from the UCSD bring up the most significant difference to date in their paper published in Nature: The immune system rejects the iPSCs more vigorously than it does the ESCs.

Here is what they did. They injected mouse ESCs and iPSCs into genetically identical mice. In theory, the cells are exactly the same as the host. Therefore, they should not trigger the burglar alarm and live happily. This is what happens with the ESCs. They are not rejected. iPSCs, however, are hunted and killed.

Obviously, this does not bode well for the plan outlined above. If the iPSCs will be rejected once we inject them, the immune system of the patient will need to be kept at bay like in the current protocols.

As you may know, there is a discussion in the US on whether to allow the use of federal grants for ESC research or not. Experiments to make patient specific ESCs using the somatic cell nuclear transfer (SCNT) technique has largely been abandoned since the invention of the iPSCs. Both because it is not easy and it requires the use of private funds. The most significant implication of this paper is that the iPSC technology is not a perfect substitute for ESC research and further research in both areas is still necessary.

One important question remaining is what would happen if one injected a differentiated cell type (heart tissue for example) into identical mice. Would tissues coming from iPSCs still be rejected more rigorously than those coming from the ESCs or would they be equivalent? In fact, I would argue that this is the more relevant question, because in future clinical applications only differentiated cells will be transplanted, not the pluripotent cells. In the paper, teratomas that come from the iPSCs had more immune cells crawling in them, suggesting the results would be similar for differentiated cells also, but I still think it is worth doing the experiment.

Formation of teratomas is a risk factor for the eventual transplantation of organs from pluripotent sources. So, if after these experiments we find out that differentiated cells from iPSCs are accepted as readily as their cousins coming from the ESCs, due to the decreased chance of teratoma formation, iPSCs might be the better source for patient specific tissue creation.