Cell Stem Cell
Volume 9, Issue 2, 5 August 2011, Pages 156-165
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Article
Unexpected X Chromosome Skewing during Culture and Reprogramming of Human Somatic Cells Can Be Alleviated by Exogenous Telomerase

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Summary

Somatic tissues in female eutherian mammals are mosaic due to random X inactivation. In contrast to mice, X chromosome reactivation does not occur during the reprogramming of human female somatic cells to induced pluripotent stem cells (iPSCs), although this view is contested. Using balanced populations of female Rett patient and control fibroblasts, we confirm that all cells in iPSC colonies contain an inactive X, and additionally find that all colonies made from the same donor fibroblasts contain the same inactive X chromosome. Notably, this extreme “skewing” toward a particular dominant, active X is also a general feature of primary female fibroblasts during proliferation, and the skewing seen in reprogramming and fibroblast culture can be alleviated by overexpression of telomerase. These results have important implications for in vitro modeling of X-linked diseases and the interpretation of long-term culture studies in cancer and senescence using primary female fibroblast cell lines.

Highlights

► Expression of a particular X confers an advantage during reprogramming into iPSCs ► Fibroblasts that express the “unfavored X” are lost during in vitro culture ► The lost population can be restored via forced reactivation of both Xs in iPSCs ► Skewing can be alleviated by overexpression of human telomerase

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