Abstract
Recent studies have suggested distinctive biological properties and signaling mechanisms between human and mouse embryonic stem cells (hESCs and mESCs). Herein we report that Shp2, a protein tyrosine phosphatase with two SH2 domains, has a conserved role in orchestration of intracellular signaling cascades resulting in initiation of differentiation in both hESCs and mESCs. Homozygous deletion of Shp2 in mESCs inhibited differentiation into all three germ layers, and siRNA-mediated knockdown of Shp2 expression in hESCs led to a similar phenotype of impaired differentiation. A small molecule inhibitor of Shp2 enzyme suppressed both hESC and mESC differentiation capacity. Shp2 modulates Erk, Stat3 and Smad pathways in ES cells and, in particular, Shp2 regulates BMP4-Smad pathway bi-directionally in mESCs and hESCs. These results reveal a common signaling mechanism shared by human and mouse ESCs via Shp2 modulation of overlapping and divergent pathways.
Highlights
The establishment of human embryonic stem cell lines has generated a great deal of excitement in the fields of stem cell biology and regenerative medicine [1]
Blastocysts were collected in M2 medium, and seeded on irradiated mouse embryonic fibroblasts (MEFs) in standard mouse ES cells (mESCs) medium supplemented with leukemia inhibitory factor (LIF) (1,000 U/ml), for growth and expansion of mESCs
The homozygous mutant mESC lines for exon 3 deletion were isolated upon selection of heterozygous mutant cells with high dosages of G418, which may induce chromosome loss in ES cells
Summary
The establishment of human embryonic stem cell (hESC) lines has generated a great deal of excitement in the fields of stem cell biology and regenerative medicine [1]. The intracellular signaling mechanisms that regulate hESC pluripotency and differentiation are poorly understood, partly due to difficulties in manipulating this type of stem cells in vitro. In the past few years, much attention has been paid to transcription factors, such as Oct, Sox and Nanog, which are essential for the establishment of human and mouse ES cell identity. These factors are found to co-occupy a substantial portion of their target genes [2,3]. It has been noted that a large set of developmental genes must be repressed in hESCs to maintain pluripotency, and their activation leads to ES cell differentiation [4]. The cytoplasmic signaling cascades controlling hESC activities are largely unknown
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