For IPS cell mutations, some reassuring new data but validation still key

Over the years some scientists including yours truly have expressed concerns about the possibility that mutations could crop up during the reprogramming process to make induced pluripotent stem cells (IPS cells or IPSC). How concerned should we be about IPS cell mutations?

A cool new paper, Bhutani, et al, in Nature Communications from a team led by Jeanne Loring and Nicholas J. Schork presents data arguing against significant oncogenic mutations occurring during reprogramming to make IPSC.

The authors summarize their findings this way:

“Our results show a moderate number of variants in the iPSCs that were not evident in the parental fibroblasts, which may result from reprogramming. There were only small differences in the total numbers and types of variants among different reprogramming methods. Most importantly, a thorough genomic analysis showed that the variants were generally benign. We conclude that the process of reprogramming is unlikely to introduce

variants that would make the cells inappropriate for therapy.”

The paper, entitled “Whole-genome mutational burden analysis of three pluripotency induction methods” does a strong job at probing the potential genomic changes associated with reprogramming including three different reprogramming methods.

I found it surprising in a good way that the retroviral approach didn’t cause more genomic issues: “Our results using retroviral vectors showed that this method caused a similar number of mutations as the other methods, but was slightly more likely to introduce mutations that are classified as deleterious.”

When mutations were found in a general sense, they tended not to be functionally associated with cancer, which is reassuring. Mutations may not be caused by reprogramming very often per se, but rather may be primarily a function of cell doublings. In this sense the situation with IPS cells is pretty similar to that with ES cells.

The derivation and culture expansion processes for stem cells over time are going to increase the chance of mutations. The bottom line is that if a team has clinical plans for human pluripotent stem cells including IPS cells they need to rigorously evaluate those cells including genetically and epigenetically, consider passage number and the possible need for post-expansion/differentiation re-validation, and focus on those lines validated to be the best.