We now know, that pluripotent (embryonic and iPS) stem cells are prone to acquisition of mutations during propagation in culture. We also know that adult stem cells can undergo spontaneous transformation. But we still don’t know about genomic stability of pluripotent stem cells derivatives – the cells which we intend to use for therapy. The recent study by Nathalie Lefort’s group, published in Journal of Clinical Investigation, shed some light on this problem. The brief summary of their findings:
- Neural stem cells, derived from human embryonic stem (ES) cells frequently acquire genomic mutations;
- Duplication of chromosome 1q was observed in non-random pattern regardless of genetic origin;
- This type of mutation was specific for neural stem cell derivatives only and was not observed in original ES and iPS cells;
- Genomic instability appeared in late passages (15-65) of neural derivatives, but not in early passages (10-22);
- Some other types of mutations were observed;
- These mutations gave a growth advantage in culture;
- Mutation was associated with loss of senescence;
- Neural stem cells carrying the mutation failed to engraft in mouse brain:
In order to determine long-term consequences of the 1q duplication, we also implanted VUB01-NSCs carrying the defect or not into the brains of 10 adult female nude rats. At 7 weeks after transplantation, nonaffected grafted cells were recovered in all cases. In contrast, NSCs carrying the 1q duplication systematically failed to integrate and expand in the host brain.
The authors pointed to 4 clinical trials, involved neural derivatives of human ES cells – 3 Advanced Cell Technology’s and 1 Geron’s trial. Well, eye cells are neural derivatives, can’t argue. The message of the study is a call for extreme caution for use of ES- and iPS cell-derivatives in clinical trials without monitoring of genomic stability. We should develop the assays for genomic stability of pluripotent cells derivatives as soon as possible.
I highly recommend you to read a commentary by Neil Harrison:
Although the chromosomal changes detected by Varela and colleagues are considered undesirable in a therapeutic setting, the inconvenient truth is that they may be inescapable, and merely demonstrate the fundamental process of natural selection. Evolutionary influences act in all living systems, with random mutation creating variants better suited to growth in a given environment. In vitro, this process has been termed culture adaptation, and it has already been reported in a number of cell types, including human ES cells.
Regardless of the tumorigenic properties of these cells, this is an alarming observation, given that the raison d’etre for these cells is to create functional neurons.
For those keen on taking ES cell–derived products to the clinic, the data generated by Varela and colleagues are clearly concerning.
Well, more trouble for ES/ iPS cell-based products developers.
Related posts:
- Direct comparison of human pluripotent stem cell derivatives with tissue-derived counterparts
- Dying hopes for iPS cell-based therapies – more on genomic instability
- An improved technique for chromosomal analysis of human pluripotent stem cells – protocol
- The pattern of genetic alterations in cultured human pluripotent stem cells
- Genomic stability of clinical-grade mesenchymal stromal cells – a proposal for international initiative
