Signaling Control of Differentiation of Embryonic Stem Cells toward Mesendoderm

•Regulatory mechanisms of different signals are involved in ME specification.•Transforming growth factor-β/Activin signaling and Wnt signaling are the most critical extrinsic signals for ME specification.•Intrinsic epigenetic regulation is important in ME determination.•Current understanding on the extrinsic and intrinsic regulations of ES cells-to-ME differentiation and the crosstalk among them is summarized here.

Mesendoderm (ME) refers to the primitive streak in mammalian embryos, which has the ability to further differentiate into mesoderm and endoderm. A better understanding on the regulatory networks of ME differentiation of embryonic stem (ES) cells would provide important insights on early embryo patterning and a possible guidance for ES applications in regenerative medicine. Studies on developmental biology and embryology have offered a great deal of knowledge about key signaling pathways involved in primitive streak formation. Recently, various chemically defined recipes have been formulated to induce differentiation of ES cells toward ME in vitro, which greatly facilitate the elucidation of the regulatory mechanisms of different signals involved in ME specification. Among the extrinsic signals, transforming growth factor-β/Activin signaling and Wnt signaling have been shown to be the most critical ones. On another side, intrinsic epigenetic regulation has been indicated to be important in ME determination. In this review, we summarize the current understanding on the extrinsic and intrinsic regulations of ES cells-to-ME differentiation and the crosstalk among them, aiming to get a general overview on ME specification and primitive streak formation.

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