Abstract
BackgroundThree types of cell lines have been established from mouse blastocysts: embryonic stem (ES) cells, trophoblast stem (TS) cells, and extra-embryonic endoderm (XEN) cells, which have the potential to differentiate into their respective cognate lineages. ES cells can differentiate in vitro not only into somatic cell lineages but into extra-embryonic lineages, including trophectoderm and extra-embryonic endoderm (ExEn) as well. TS cells can be established from ES cells by the artificial repression of Oct3/4 or the upregulation of Cdx2 in the presence of FGF4 on feeder cells. The relationship between these embryo-derived XEN cells and ES cell-derived ExEn cell lines remains unclear, although we have previously reported that overexpression of Gata4 or Gata6 induces differentiation of mouse ES cells into extra-embryonic endoderm in vitro.ResultsA system in which GATA factors were conditionally activated revealed that the cells continue to proliferate while expressing a set of extra-embryonic endoderm markers, and, following injection into blastocysts, contribute only to the extra-embryonic endoderm lineage in vivo. Although the in vivo contribution is limited to cells of parietal endoderm lineage, Gata-induced extra-embryonic endoderm cells (gExEn) can be induced to differentiate into visceral endoderm-like cells in vitro by repression of Gata6. During early passage, the propagation of gExEn cells is dependent on the expression of the Gata6 transgene. These cells, however, lose this dependency following establishment of endogenous Gata6 expression.ConclusionWe show here that Gata-induced extra-embryonic endoderm cells derived from ES cells mimic the character of XEN cells. These findings indicate that Gata transcription factors are sufficient for the derivation and propagation of XEN-like extra-embryonic endoderm cells from ES cells.
Highlights
Three types of cell lines have been established from mouse blastocysts: embryonic stem (ES) cells, trophoblast stem (TS) cells, and extra-embryonic endoderm (XEN) cells, which have the potential to differentiate into their respective cognate lineages
Continuous propagation of extraembryonic endoderm (ExEn) cells induced from ES cells by ectopic expression of Gata4 or Gata6 By functional screening of transcription factors whose expression is upregulated after induction of differentiation in ES cells, we found that the GATA-family transcription factors Gata4 and Gata6 could induce differentiation toward the ExEn lineage [10]
Upon ectopic expression of Gata4 or Gata6, ES cells differentiated into dispersed refractive cells that resembled parietal endoderm (PE) cells and expressed PE marker genes such as Sparc and Plat, indicating that activation of Gata4 and Gata6 is sufficient for inducing PE-like ExEn differentiation in ES cells
Summary
Three types of cell lines have been established from mouse blastocysts: embryonic stem (ES) cells, trophoblast stem (TS) cells, and extra-embryonic endoderm (XEN) cells, which have the potential to differentiate into their respective cognate lineages. TS cells can be established from ES cells by the artificial repression of Oct3/4 or the upregulation of Cdx in the presence of FGF4 on feeder cells The relationship between these embryo-derived XEN cells and ES cell-derived ExEn cell lines remains unclear, we have previously reported that overexpression of Gata or Gata induces differentiation of mouse ES cells into extra-embryonic endoderm in vitro. VE forms layers of columnar epithelial cells covering the epiblast and contributes to the visceral yolk sac, while PE migrates along the surface of the inner TE, secreting extracellular matrix to form the Reichert's membrane and contributes to parietal yolk sac as well [2] These ExEn lineage cells are important in embryonic development, as nutritive supports and as a determinant of the anterior-posterior axis
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