MEK1/2 and GSK3b inhibitors enhance the derivation of mouse embryonic stem cells (mES cells) in a ground state of pluripotency that closely resembles the inner cell mass of the pre-implantation embryo. However, the effect of long-term culture under these conditions on the developmental potential of mES cells is unclear. Konrad Hochedlinger and colleagues show that these culture conditions lead to detrimental changes in epigenetic features, genomic stability and in vivo developmental potential. The authors find that MEK inhibitors trigger changes in DNA methyltransferase expression that are linked to the observed abnormalities and show that using a Src inhibitor instead prevents the development of these abnormalities, preserving the genomic integrity and developmental potential of the ES cells. Elsewhere in this issue, Yashuiro Yamada and colleagues show that derivation of female mES cells under these culture conditions induces a loss of DNA methylation and erasure of genomic imprints, which are not recovered following differentiation. The team also develops a culture medium that preserves genomic features of a female ES cell.
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