Mutation frequency dynamics in HPRT locus in culture adaptedhESCs and iPSCs correspond to their differentiated counterparts
Stem Cells and Development(2014)
摘要
The genomic destabilization associated with the adaptation of
human embryonic stem cells (hESCs) to culture conditions or the
reprogramming of induced pluripotent stem cells (iPSCs)
increases the risk of tumorigenesis upon the clinical use of
these cells and decreases their value as a model for cell
biology studies. Base excision repair (BER), a major genomic
integrity maintenance mechanism, has been shown to fail during
hESC adaptation. Here, we show that the increase in the
mutation frequency (MF) caused by the inhibition of BER was
similar to that caused by the hESC adaptation process. The
increase in MF reflected the failure of DNA maintenance
mechanisms and the subsequent increase in MF rather than being
due solely to the accumulation of mutants over a prolonged
period, as was previously suggested. The increase in the
ionizing radiation-induced MF in adapted hESCs exceeded the
induced MF in non-adapted hESCs and differentiated cells.
Unlike hESCs, the overall DNA maintenance in iPSCs, which was
reflected by the MF, was similar to that in differentiated
cells regardless of the time spent in culture and despite the
upregulation of several genes responsible for genome
maintenance during the reprogramming process. Taken together,
our results suggest that the changes in BER activity during the
long-term cultivation of hESCs increase the mutagenic burden,
whereas neither reprogramming nor long-term propagation in
culture changes the MF in iPSCs.
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