Collagen IV Induces Trophoectoderm Differentiation of Mouse Embryonic Stem Cells

Abstract

The earliest segregation of lineages in the developing embryo is the commitment of cells to the inner cell mass or the trophoectoderm in preimplantation blastocysts. The exogenous signals that control commitment to a particular cell lineage are poorly understood; however, it has been suggested that extracellular "niche" and extracellular matrix, in particular, play an important role in determining the developmental fate of stem cells. Collagen IV (ColIV) has been reported to direct embryonic stem (ES) cell differentiation to mesodermal lineages in both mouse and human ES cells. To define the effects of ColIV on ES cell differentiation and to identify the resulting heterogeneous cell types, we performed microarray analyses and determined global gene expression. We observed that ColIV induced the expression of mesodermal genes specific to hematopoietic, endothelial, and smooth muscle cells and, surprisingly, also a panel of trophoectoderm-restricted markers. This effect was specific to collagen IV, as no trophoblast differentiation was seen on collagen I, laminin, or fibronectin. Stimulation with basic fibroblast growth factor (FGF) or FGF4 increased the number of trophoectodermal cells. These cells were isolated under clonal conditions and successfully differentiated into a variety of trophoblast derivatives. Interestingly, differentiation of ES cells to trophoblastic lineages was only seen in ES cell lines maintained on embryonic feeder layers and was caudal-type homeobox protein 2 (Cdx2)-dependent, consistent with Cdx2's postulated role in trophoectoderm commitment. Our data suggest that, given the appropriate extracellular stimuli, mouse embryonic stem cells can differentiate into trophoectoderm. STEM CELLS

Conversion from mouse embryonic to extra-embryonic endoderm stem cells reveals distinct differentiation capacities of pluripotent stem cell states

“…Interestingly, mESCs may also generate trophoblast-like cells without genetic manipulation (Schenke-Layland et al, 2007;He et al, 2008). Altogether, our work further suggests that mESCs have a greater differentiation capacity than has been previously appreciated.…”

Human Embryonic Stem Cells as Models for Trophoblast Differentiation

“…A similar up-regulation of trophoblast markers and a transition in cell morphology was observed after NANOG silencing [39], although markers of extra-embryonic endoderm as well as those of trophoblast were increased. There is some evidence that mouse ESC can differentiate to trophoblast under certain conditions, but this process does not appear to occur as readily as in primate cells [40,41]. Studies in the mouse have largely concentrated on trophoblast stem cells [42], whose equivalent has as yet not been reported for the human.…”

Cdx2Efficiently Induces Trophoblast Stem-Like Cells in Naïve, but Not Primed, Pluripotent Stem Cells

“…Knowledge of signaling pathways and transcription factors that reinforce these three lineages in the blastocyst has pointed to ways to alter the developmental potential of the stem cell lines derived from the blastocyst's lineages. For example, ESCs can be converted to TSCs by overexpressing the TE-specific transcription factor CDX2 in TSC medium [16] and by other means [17][18][19][20][21]. Importantly, overexpression of Cdx2 in ESCs leads to TSC-like cells with highly similar morphology, developmental potential, and gene expression as embryoderived TSCs [16,22,23].…”