Are iPSCs safe? Nearly 75% of Skin Stem Cells Have Severe DNA Damage from UV Exposure

Stem cells are important tools in the field of regenerative medicine. In addition to their regenerative capacity, these cells can also differentiate into other types of somatic cells, among which induced pluripotent stem cell (iPSC), a new generation of technologically induced multifunctional stem cells, can be genetically modified to return differentiated cells to their pre-differentiated stem cells.

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Despite the contribution of iPSC to stem cell applications, a recent large-scale iPSC genomic study at the University of Cambridge found that nearly 3/4 of skin-derived stem cells were found to have severe DNA damage. They theorize that this phenomenon may be due to frequent skin exposure to external UV radiation. Given the increased risk of developing cancers with the accumulation of mutations, careful selection of the source of stem cells and confirmation of safety are of great importance. The results of this study were recently published in Nature Genetics.

Severe DNA Damage Found in Nearly 75% of Skin iPSCs

In order to conduct a large-scale analysis of the genomic characteristics of human iPSCs (hiPSCs), the Cambridge University team collected a total of nearly 700 cell lines from two iPSC banks and performed a genomic comparison of subclone cells derived from these cell lines. Overall, they found that even iPSCs from the same patient were genetically damaged to varying degrees depending on the distribution of cells.

The results indicate that fibroblast-derived hiPSCs have significant DNA mutations (up to 15 mutations per megabase) and that up to 72% of skin iPSCs have severe DNA damage due to UV exposure. This is an alarming observation as the number of mutations found in these cell lines derived from skin biopsies of healthy people is even higher than that in some tumor tissues from cancer patients.

Mutations in Blood iPSCs Independent of UV Stimulation

The team also analyzed blood-derived hiPSCs and found that they had fewer mutations than fibroblast-derived hiPSCs and found no UV-related damage. However, it should be noted that about 25% of blood-derived hiPSCs have BCOR mutations, a commonly found mutation in hematological cancers, and that iPSCs with BCOR mutations tend to produce “extra-neuronal” cells during the process of differentiation. The frequency of this mutation will also accumulate even in cells without BCOR mutations during cell culture expansion.

Prof. Serena Nik-Zainal, the project leader, concluded that as stem cell applications become more widespread, the importance of whole genome sequencing of cells before treatment has become more evident. This is not only true for those working in the field of neuronal stem cell and blood stem cell research, but essentially all cell lines of iPSCs are at risk of harboring mutated genes. Thus, it would be more pragmatic to learn as much as possible about the nature and extent of DNA damage to make a safer and more reliable choice of cell lines.

Author

Richard Chau