Induced pluripotent stem cells rejected by mouse immune system

A recent paper in the journal Nature by Yang Xu and colleagues from the University of California, San Diego has shown that induced pluripotent stem cells (iPSCs) made from mouse embryonic skin cells made tumors called teratomas when injected into those same mice that were attacked by the mouse’s immune system. This paper has questioned whether iPSCs can be used for therapeutic purposes in human patients.

This conclusion, however, does not necessarily follow. In the first place, this work derived its iPSCs not from mature adult cells, but from embryonic cells. Secondly, the transplanted cells were not differentiated cells, but were stem cells, which are known to form teratomas when transplanted into laboratory animals. Because teratomas have the capacity to grow into various tissues, they are invaders. Secondly, they almost certainly express surface proteins that the immune system has never seen before. This would probably induce the immune system to attack the teratoma.

Secondly, many papers have transplanted differentiated iPSCs into rodents with no reports of rejection by the immune system (reviewed in Timothy J. Nelson, “Induced pluripotent stem cells: advances to applications,” Stem Cells and Cloning Stem 3 (2010): 29-37). Surely, this paper represents a non-analogous circumstance that has cast aspersions on a completely different clinical application.

Swedish group also Converts Skin Cells into Brain Cells

Researchers at Lund University in Sweden have also successfully transdifferentiated skin cells into functional nerve cells. This confirms the work of the Stanford University scientists who reported similar success. Interestingly, the Swedish group showed that this transdifferentiation protocol is rather simple.

The beauty of transdifferentiation is that it completely bypasses all the ethical problems of embryonic stem cells. Malin Parmar, head of the Swedish research group said, “We didn’t really believe this would work, to begin with it was mostly just an interesting experiment to try. However, we soon saw that the cells were surprisingly receptive to instructions.”

Parmar’s group overexpressed three genes (Ascl1, Brn2, and Myt1l) in fibroblasts, and these genes transformed the fibroblasts into neurons. Then by overexpressing two more genes (Lmx1a and FoxA2) converted the neurons into dopamine-producing neurons. These types of neurons are exactly the ones that die in the brains of patients suffering from Parkinson/’s disease. While transplants of dopamine-producing cells into the brains of animals with Parkinson’s disease, the problem with these types of treatments is that they require large quantities of cells for transplantations. While embryonic stem cells can be grown in large quantities, they have ethical problems and the potential for tumor production. Because fibroblasts can be grown in large quantities and recovered from small punch biopsies, they can be grown into large quantities of cells. Also, these experiments completely bypassed the embryonic stage, and therefore, bypass the risk of tumor formation.

The vision for the future is that physicians can produce brain cells that patients need from a simple skin or hair sample. These specifically designed cells that originate from the patient would be accepted better by the body’s immune system than transplanted cells from donor tissue.

Parmar noted, “This is the big idea in the long run. We hope to be able to do a biopsy on a patient, make dopamine cells, for example, and then transplant them as a treatment for Parkinson’s disease.” Parmar and his group is now continuing the research to develop more types of brain cells using the new technique.