Some thoughts on the Araki Nature iPS cell paper: an advance, but a few key caveats

I’ve already talked with science writer Ed Yong about the new Nature paper Araki, et al. (you can read Ed’s well-written piece here and you can another one on it by another one of my favorite writers, Monya Baker here), which suggests that iPS cells don’t trigger much in the way of an immune response.

I think the Araki paper is important and encouraging that iPS cell derivative tissues may not be any more immunogenic than those made from ES cells, but it is far from definitive for a number of reasons.

First, what is in the paper?

The reported minimal immunogenicity of iPS-derived tissues transplanted into syngeneic recipients is particularly notable because it strongly suggests that future human iPS cell-derived therapies given back to the same human patient might not trigger a clinically significant immune response. If this proves to be the case, human iPS cell therapies would have an advantage over embryonic stem cell (ESC)-based therapies, which are inherently allogeneic (unmatched, non-self). However, interestingly, patients in the now halted Geron and continuing Advanced Cell Technology (ACT) human ESC-based clinical trials have reportedly done well with only transient immunosuppression following transplant.

In addition, because all the data reported in the Akari study are derived from experiments on mouse cells and mice, the immunogenicity of transplanted human iPS cells was not directly addressed in these studies nor has it been examined in other published studies to my knowledge.

Another notable limitation of the current study is that its assessment of the potential immunogenicity of iPS cell-derived tissues, while comprehensive (assays using teratoma, transplanted surgically excised skin, and bone marrow transplant) did not make use of in vitro derived differentiated cells produced from iPS cells in the lab. This distinction is important because as one imagines future clinical use of iPS cell-based treatments in human patients, the vast majority of such therapies would utilize in vitro differentiated cells or tissues produced from iPS cells in the lab, which could have a higher intrinsic immunogenicity due to their time cultured in a lab. The transplanted tissues from chimeric mice in the reported experiments might have already somehow eliminated immunoreactive iPS-derived cells as well.

Another interesting conclusion of the paper is that iPS cells and ESCs have essentially equivalent immunogenicity (low-to-nearly absent), suggesting that the cellular reprogramming process is not inherently one that leads to relatively high levels of immunogenicity. In addition, the team found variability amongst different clonal lines of iPS cells or ESCs; I found in intriguing that they suggested that incomplete reprogramming in some clones might yield higher immunogenicity.

Bottom line? While the paper is just one step on the path to translating these iPS cells from the bench to the bedside, it is a novel and significant advance in my opinion. I can’t wait to see more in this area be published!

2 thoughts on “Some thoughts on the Araki Nature iPS cell paper: an advance, but a few key caveats

  1. Thanks for your thoughts on this paper Paul. But it looks to me like the two groups saw roughly equal rejection of integration-free iPSC-derived teratomas. Araki et al. report 80% teratoma formation from iPSCs in Fig 1a and Zhao et al. report 80% “growing tumor” from iPSCs in Fig 3c. The real difference seems to be that Araki reports rejection of ~30% of ESC-derived teratomas while Zhao does not. I may be missing something, but it strikes me as funny that those data resulted in such different titles.

    Also, while neither teratoma injection, nor transplantation of iPSC-derived chimera-matured cells is the killer experiment, Abe did at least attempt the killer experiment! They differentiated iPSCs into cardiomyocytes in vitro and transplanted them… and saw “significant levels of T-cell infiltration” (Supp Fig 13). Oops! Maybe they should have re-thought the paper title?

    • I agree with you Zach on the title of the paper. I think it over-reached. I do think the tissue transplant part is more interesting than the teratoma part of this new paper. My hunch is that both iPS and ES cell-derived cells and tissues will in a context dependent manner evoke modest, but not absent immune responses….but will the responses to be clinically relevant for iPS cell-derived products transplanted in a syngeneic manner? I don’t know for sure. Hopefully not.

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