Hormonal induction of differentiation in teratocarcinoma stem cells: Generation of parietal endoderm by retinoic acid and dibutyryl cAMP

doi:10.1016/0092-8674(80)90471-7

Cell

Volume 21, Issue 2, September 1980, Pages 347-355

https://doi.org/10.1016/0092-8674(80)90471-7 Get rights and content

Abstract

It has previously been shown that retinoic acid induces multiple phenotypic changes in cultures of F9 teratocarcinoma stem cells. In this paper we demonstrate that these retinoid-generated cells can be converted to yet another cell type by compounds that elevate cAMP concentrations. The phenotype of the new cell type is characterized by the synthesis of plasminogen activator, laminin and type IV collagen, and by very low levels of alkaline phosphatase and lactate dehydrogenase. The secretion of plasminogen activator and type IV collagen, and low levels of alkaline phosphatase and lactate dehydrogenase, have been previously shown to be properties of parietal endoderm, an extraembryonic cell which is generated early in mouse embryogenesis. We show here that parietal endoderm also synthesizes laminin. The cell type generated by retinoic acid and dibutyryl cAMP treatment is therefore indistinguishable from definitive parietal endoderm. Analysis of the final phenotype indicates that it is not dependent upon the continued presence of either compound, and that cAMP agents are active only on cells that have been treated with retinoic acid.

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Citation Excerpt :
To test this F9 cells were cultured in monolayer in the presence of RA (10−7 M) alone for 2 days followed by the replacement with fresh medium containing RA (10−7 M) and db-cAMP (10−3 M) and cultivation for another 3 days to induce ExEn differentiation. Under these conditions, cells in monolayer culture differentiate into PrE and PE but are also able to build up VE coinciding with previous reports (Inoue et al., 2009; Strickland and Mahdavi, 1978; Strickland et al., 1980). Expression of ExEn marker genes and the level of active β-Catenin as a marker for Wnt signaling were monitored (Fig. 1A).
Mouse F9 teratocarcinoma cells are an established model for the differentiation of extra-embryonic endoderm (ExEn). Primitive endoderm, parietal and visceral endoderm can be generated by stimulation of F9 cells with retinoic acid and dibutyryl cyclic adenosine monophosphate. Here we show that Wnt/β-Catenin signaling is down-regulated during ExEn differentiation in F9 cells and that the inhibition of the Wnt pathway promotes differentiation of the three extra-embryonic endoderm lineages. Wnt inhibition is achieved through the IGF pathway, which is up-regulated during differentiation. IGF signaling antagonizes the Wnt pathway by stimulating transcription of axin2 and by stabilizing Axin1 protein. Both Axin1 and Axin2 are components of the β-Catenin destruction complex and act as intra-cellular inhibitors of the Wnt/β-Catenin pathway. The data presented reveal a mechanism which restricts pluripotency of undifferentiated cells and directs them toward extra-embryonic lineages.
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Pluripotent stem cells maintain their pluripotency and undifferentiated status through a network of transcription factors. Liver receptor homolog-1 (Lrh-1) is one of these, and regulates the expression of other important transcription factors such as Oct-3/4 and Nanog. In early embryo and embryonic stem (ES) cells, Lrh-1 is transcribed using a unique promoter. In this study, we investigated the transcriptional regulation of embryonic Lrh-1 using ES and embryonal carcinoma F9 cells. Reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays demonstrated that Sox2 and Gabp proteins bind to the promoter region of embryonic Lrh-1, and are necessary for its activation. The Sox2 site showed strong promoter activity and affinity for protein binding. Upon differentiation into the parietal endoderm by retinoic acid and cAMP, Lrh-1 promoter activity and transcripts were markedly reduced within 24 h. At the same time, Sox2 and Gabp binding to the promoter region of Lrh-1 were decreased, followed by a reduction of their expression. These results indicate that embryonic Lrh-1 expression is regulated by both Sox2 and Gabp. Our study presents new insights into the transcription factor network of pluripotent stem cells.

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ArticleHormonal induction of differentiation in teratocarcinoma stem cells: Generation of parietal endoderm by retinoic acid and dibutyryl cAMP

Abstract

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Hormonal induction of differentiation in teratocarcinoma stem cells: Generation of parietal endoderm by retinoic acid and dibutyryl cAMP