Parp1-deficiency induces differentiation of ES cells into trophoblast derivatives

Abstract

Embryonic stem (ES) cells deficient in the enzyme poly(ADP-ribose) polymerase (Parp1) develop into teratocarcinoma-like tumors when injected subcutaneously into nude mice that contain cells with giant cell-like morphology. We show here that these cells express genes characteristic of trophoblast giant cells and thus belong to the trophectoderm lineage. In addition, Parp1(-/-) tumors contained other trophoblast subtypes as revealed by expression of spongiotrophoblast-specific marker genes. The extent of giant cell differentiation was enhanced, however, as compared with spongiotrophoblast. A similar shift toward trophoblast giant cell differentiation was observed in cultures of Parp1-deficient ES cells and in placentae of Parp1(-/-) embryos. Analysis of other cell lineage markers demonstrated that Parp1 acts exclusively in trophoblast to suppress differentiation. Surprisingly, trophoblast derivatives were also detected in wildtype tumors and cultured ES cells, albeit at significantly lower frequency. These data show that wildtype ES cells contain a small population of cells with trophectoderm potential and that absence of Parp1 renders ES cells more susceptible to adopting a trophoblast phenotype.

Trophoblast Stem Cells: Models for Investigating Trophectoderm Differentiation and Placental Development

“…As mentioned earlier, OCT4 repression allows CDX2 to promote formation of the trophectoderm lineage (26). Mouse ESC lacking poly (ADP-ribose) polymerase expression show enhanced spontaneous differentiation of trophoblast giant cells (75). Recently, it has also been reported that collagen type IV, a basement membrane constituent, can direct differentiation of mouse ESC toward the trophectoderm lineage (76).…”

DNA methylation and its role in the trophoblast cell lineage

“…Parp1 -/-ES cells differentiate into trophoblast derivatives in vitro and in ES cell-derived tumors (Hemberger et al, 2003;Nozaki et al, 2013;Nozaki et al, 1999;Ogino et al, 2007). Significant upregulation of H19 in Parp1 -/-ES was detected by a microarray analysis and was then validated by RT-PCR (Ogino et al, 2007).…”

Dynamic Changes in Gene Expression during Early Trophoblast Differentiation from Human Embryonic Stem Cells Treated with BMP4

“…They require LIF/STAT3 signaling for maintenance of pluripotency (Hall, Guo et al 2009), while BMP4 provides additional support for self renewal and resistance to differentiation (Ying, Nichols et al 2003). However, mESC are generally recognized as being pluripotent rather than totipotent and only capable of contributing to the embryonic lineage and not to elements of extraembryonic tissues derived from trophectoderm (TE) (Beddington and Robertson 1989;Nagy, Gocza et al 1990), presumably because they are already stably committed offshoots of the ICM and/or its derivative, the epiblast (Rossant and Spence 1998;Hemberger, Nozaki et al 2003). ESC established from monkey and human blastocysts (Thomson, Kalishman et al 1995;Thomson, Itskovitz-Eldor et al 1998), have markedly different characteristics to mESC.…”