Unique features of mutations revealed by sequentially reprogrammed induced pluripotent stem cells
Unique features of mutations revealed by sequentially reprogrammed induced pluripotent stem cells
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顺序重编程诱导多能干细胞揭示突变的独特特征
DOI：
10.1038/ncomms7318
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发表时间：
2015-02-01
影响因子：
16.6
通讯作者：
Gao, Shaorong
中科院分区：
文献类型：
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作者：
Gao, Shuai;Zheng, Caihong;Gao, Shaorong
虽然可以从诱导多能干细胞（iPSC）中产生活的小鼠，但累积突变对所产生的iPSC发育潜力的影响仍有待确定。在这里，我们证明了通过四倍体胚泡互补产生的全iPSC小鼠可以耐受使用Tet-on诱导重编程系统累积多达六代的体细胞突变。但是，全iPS小鼠的生存能力随着世代的增加而下降。一项全基因组测序调查显示，在整个顺序重编程过程中积累了数千个单核苷酸变异（SNV），其中包括44个非同义变异。随后的分析提供了证据，这些累积的SNV解释了所得全iPSC小鼠的活力的逐渐降低。出乎意料的是，我们目前的重编程系统揭示了多能干细胞在拥有一组拷贝数改变（CNA）方面是异质的。这些CNA对于多能细胞是独特的，随后在分化的后代中消失。
Although viable mice can be generated from induced pluripotent stem cells (iPSCs), the impact of accumulated mutations on the developmental potential of the resulting iPSCs remains to be determined. Here, we demonstrate that all-iPSC mice generated through tetraploid blastocysts complementation can tolerate the accumulation of somatic mutations for up to six generations using a Tet-on inducible reprogramming system. But, the viability of the all-iPS mice decreased with increasing generations. A whole-genome sequencing survey revealed that thousands of single-nucleotide variations (SNVs), including 44 non-synonymous ones, accumulated throughout the sequential reprogramming process. Subsequent analysis provides evidence that these accumulated SNVs account for the gradual reduction in viability of the resultant all-iPSC mice. Unexpectedly, our present reprogramming system revealed that pluripotent stem cells are heterogeneous in terms of possessing a set of copy-number alterations (CNAs). These CNAs are unique for pluripotent cells and subsequently disappear in the differentiating progenies.