Abstract
SummaryPluripotent cells emanate from the inner cell mass (ICM) of the blastocyst and when cultivated under optimal conditions immortalize as embryonic stem cells (ESCs). The fundamental mechanism underlying ESC derivation has, however, remained elusive. Recently, we have devised a highly efficient approach for establishing ESCs, through inhibition of the MEK and TGF-β pathways. This regimen provides a platform for dissecting the molecular mechanism of ESC derivation. Via temporal gene expression analysis, we reveal key genes involved in the ICM to ESC transition. We found that DNA methyltransferases play a pivotal role in efficient ESC generation. We further observed a tight correlation between ESCs and preimplantation epiblast cell-related genes and noticed that fundamental events such as epithelial-to-mesenchymal transition blockage play a key role in launching the ESC self-renewal program. Our study provides a time course transcriptional resource highlighting the dynamics of the gene regulatory network during the ICM to ESC transition.
Highlights
Pluripotency is initiated in cells of the inner cell mass (ICM) and lapses shortly after implantation, coincident with the rise in lineage commitment
Pluripotent cells emanate from the inner cell mass (ICM) of the blastocyst and when cultivated under optimal conditions immortalize as embryonic stem cells (ESCs)
Via temporal gene expression analysis, we reveal key genes involved in the ICM to ESC transition
Summary
Pluripotency is initiated in cells of the inner cell mass (ICM) and lapses shortly after implantation, coincident with the rise in lineage commitment. In vitro culture of ICM permits the generation of stable self-renewing pluripotent embryonic stem cells (ESCs) (Evans and Kaufman, 1981). ESC derivation is largely dependent upon the culture conditions. Under conventional medium, containing fetal calf serum and either feeder cells or leukemia inhibitory factor (LIF), only embryos from 129/Sv strain can efficiently give rise to ESCs and most strains of mice are refractory to ESC generation (Brook and Gardner, 1997). Preventing the formation of PE cells by induction of embryonic diapause (Brook and Gardner, 1997) or use of chemical substances that inhibit Fgf signaling (Ying et al, 2008) led to the formation of preEpi cells with efficient capability to generate ESCs even in serum- and feeder-free culture conditions. As pluripotent preEpi cells do not exhibit self-renewability, per se, the mechanism underlying this in vivo to in vitro conversion remains controversial (Loh et al, 2015)
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