Not All Stem Cells Are Created Equal: Immune Rejection of iPSCs

Could induced pluripotent stem cells (iPSCs) be just as good as embryonic stem cells (ESCs) for therapeutic use? Although iPSCs have advantages for research, as they sidestep the ethical problems of ESCs and make useful disease models (see ARF related news story), their value for transplants is less certain. Current reprogramming technologies leave slight epigenetic differences between iPSCs and ESCs, which concerns some researchers. Adding fuel to the fire, scientists led by Yang Xu at the University of California in San Diego reported in the May 13 Nature that iPSCs are more likely to be rejected by the immune system than are ESCs. The authors traced this phenomenon to the expression of specific factors by the cells, which suggests that the problem might be lessened by better reprogramming technologies.

To test immunogenicity, first author Tongbiao Zhao derived ESCs and iPSCs from inbred B6 mice. To make iPSCs, he reprogrammed B6 mouse fibroblasts using either three or four genes. In one method, he delivered the reprogramming factors via a retrovirus, and in the other approach he used an episome, a piece of DNA that does not integrate into the animals’ genome. When Zhao and colleagues implanted ESCs into B6 mice, the cells formed large teratomas containing many differentiated cell types. Recognizing them as “self,” the immune system did not attack these ESC-derived teratomas. On the other hand, the animals’ immune systems mounted a fierce assault on implanted iPSCs that had been reprogrammed with retroviral vectors—even though the cells came from genetically identical animals. Teratomas either failed to form, or contained many infiltrating T cells and a lot of necrotic tissue. The immune response was gentler on iPSCs reprogrammed with non-integrating episomal vectors, suggesting that episomal-derived iPSCs are more similar to ESCs. iPSCs made with episomes formed teratomas easily, but T cells infiltrated the majority of them, and about 10 percent of teratomas became necrotic.

To discover the reason for immune system rejection, the authors compared the gene expression profiles of teratomas derived from ESCs with those from iPSCs made with episomes. They found nine genes that were commonly overexpressed in regressing teratomas formed from iPSCs. To test these genes, Zhao and colleagues expressed each one in ESCs and looked for immune rejection of the resulting teratomas. The genes Zg16 and Hormad1 were most strongly associated with rejection. “The abnormal expression of Hormad1 and Zg16 contributes directly to the immunogenicity of the cells,” the authors concluded.

This implies that reprogramming technologies may need to be optimized to reduce epigenetic differences between ESCs and iPSCs, the authors suggested, pointing out that their teratoma assay could provide a useful screening platform for improving reprogramming. Others in the field are more cautious as to whether this finding indicates a problem for iPSC transplantation, noting that the experiment involved injecting undifferentiated iPSCs. Rudolf Jaenisch at the Whitehead Institute, MIT, wrote to ARF, “In a patient, one would inject, of course, only differentiated functional cells.” (See full comment below.) In previous experiments from his group, Jaenisch said, they injected iPS cell-derived hematopoietic stem cells to correct sickle cell anemia in a mouse model, and saw no immune rejection, suggesting that differentiated cells are not immunogenic (see Hanna et al., 2007). Xu disagrees, writing to ARF that, because the iPSCs differentiate into numerous cell types in the teratomas, “in our immunogenicity assay, we were simultaneously evaluating the immune responses to almost all the differentiated cell types present in the body. There are very few iPSCs in the teratomas, so the immune reactions detected are against the differentiated cell types.”

Mahendra Rao, vice president of stem cells at biotech company Life Technologies, agreed with Jaenisch that the immunogenicity of pre-differentiated cells is the key question. Rao wrote to ARF, “It is too early to suggest that this will change our view of either ESCs or iPSCs in any fundamental way.” (See full comment below.) Many labs are using iPSCs derived from people with various disorders to create models for a range of neurodegenerative diseases (see ARF related series). This work should not be affected by the new findings.

Zhao T, Zhang ZN, Rong Z, Xu Y. Immunogenicity of induced pluripotent stem cells. Nature. 2011 May 13. Abstract

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