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

Douglas, Gordon C.; VandeVoort, Catherine A.; Kumar, Priyadarsini; Chang, T. Arthur; Golos, Thaddeus G.

doi:10.1210/er.2009-0001

Cited by 69 publications

(51 citation statements)

References 105 publications

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“…As discussed earlier, the idea that BMP4 can drive hESCs to trophoblast has been controversial (31), despite evidence that both mouse ESCs and hESCs have the potential to differentiate along extraembryonic lineages under appropriate culture conditions (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Moreover, recent evidence suggests that BMP signaling has a role in ensuring the correct development of the trophoblast lineage in preimplantation mouse embryos (59,60) and that, by the 16-cell morula stage, only the outer cells are fully equipped to respond to signals initiated by BMP4 and related ligands, such as BMP7 (59).…”

Section: Discussionmentioning

confidence: 99%

“…hESCs and iPSCs will also differentiate to the extraembryonic trophoblast lineage either when they are allowed to form embryoid bodies (12,13) or when BMP4, or certain of its homologs, including BMP2, BMP5, BMP7, BMP10, and BMP13, are present in the medium and FGF2 is absent (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). The BMPdriven process is accelerated and directionality is enhanced if the signaling pathways that maintain the pluripotent state are inhibited (25).…”

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confidence: 99%

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Heightened potency of human pluripotent stem cell lines created by transient BMP4 exposure

Yang

Adachi

Sheridan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Human pluripotent stem cells (PSCs) show epiblast-type pluripotency that is maintained with ACTIVIN/FGF2 signaling. Here, we report the acquisition of a unique stem cell phenotype by both human ES cells (hESCs) and induced pluripotent stem cells (iPSCs) in response to transient (24-36 h) exposure to bone morphogenetic protein 4 (BMP4) plus inhibitors of ACTIVIN signaling (A83-01) and FGF2 (PD173074), followed by trypsin dissociation and recovery of colonies capable of growing on a gelatin substratum in standard medium for human PSCs at low but not high FGF2 concentrations. The self-renewing cell lines stain weakly for CDX2 and strongly for NANOG, can be propagated clonally on either Matrigel or gelatin, and are morphologically distinct from human PSC progenitors on either substratum but still meet standard in vitro criteria for pluripotency. They form well-differentiated teratomas in immune-compromised mice that secrete human chorionic gonadotropin (hCG) into the host mouse and include small areas of trophoblast-like cells. The cells have a distinct transcriptome profile from the human PSCs from which they were derived (including higher expression of NANOG, LEFTY1, and LEFTY2). In nonconditioned medium lacking FGF2, the colonies spontaneously differentiated along multiple lineages, including trophoblast. They responded to PD173074 in the absence of both FGF2 and BMP4 by conversion to trophoblast, and especially syncytiotrophoblast, whereas an A83-01/PD173074 combination favored increased expression of HLA-G, a marker of extravillous trophoblast. Together, these data suggest that the cell lines exhibit totipotent potential and that BMP4 can prime human PSCs to a self-renewing alternative state permissive for trophoblast development. The results may have implications for regulation of lineage decisions in the early embryo.biological sciences | developmental biology | pluripotent stem cells | totipotent | trophoblast

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Heightened potency of human pluripotent stem cell lines created by transient BMP4 exposure

Yang

Adachi

Sheridan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Fundamental insights into the molecular control of trophectoderm determination and differentiation have been made in the past decade Douglas et al, 2009;Ralston and Rossant, 2005). A number of transcription factors and signaling pathways have been identified as crucial players.…”

Section: Trophoblast Stem Cellsmentioning

confidence: 99%

Small RNAs in early mammalian development: from gametes to gastrulation

2011

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Small non-coding RNAs, including microRNAs (miRNAs), endogenous small interfering RNAs (endo-siRNAs) and Piwiinteracting RNAs (piRNAs), play essential roles in mammalian development. The function and timing of expression of these three classes of small RNAs differ greatly. piRNAs are expressed and play a crucial role during male gametogenesis, whereas endo-siRNAs are essential for oocyte meiosis. By contrast, miRNAs are ubiquitously expressed in somatic tissues and function throughout post-implantation development. Surprisingly, however, miRNAs are non-essential during preimplantation embryonic development and their function is suppressed during oocyte meiosis. Here, we review the roles of small non-coding RNAs during the early stages of mammalian development, from gamete maturation through to gastrulation.

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“…This differentiation occurred without extensive generation of mesoderm, endoderm, and ectoderm derivatives, as judged by microarray analysis of transcribed genes, although a low level of expression of genes characteristic of mesoderm and endoderm did occur. This model has become widely used (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) to study an aspect of early human development that is not easily addressed otherwise because of lack of access to human embryos. Over the course of these studies it was demonstrated that the key to obtaining differentiation primarily to TR rather than to other lineages when using BMP4 as the triggering agent was to exclude FGF2, a factor required for maintenance of hESC (14)(15)(16)(17).…”

mentioning

confidence: 99%

Complete and unidirectional conversion of human embryonic stem cells to trophoblast by BMP4

Amita

Adachi

Alexenko

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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307

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Human ES cells (hESC) exposed to bone morphogenic protein 4 (BMP4) in the absence of FGF2 have become widely used for studying trophoblast development, but the soundness of this model has been challenged by others, who concluded that differentiation was primarily toward mesoderm rather than trophoblast. Here we confirm that hESC grown under the standard conditions on a medium conditioned by mouse embryonic fibroblasts in the presence of BMP4 and absence of FGF2 on a Matrigel substratum rapidly convert to an epithelium that is largely KRT7+ within 48 h, with minimal expression of mesoderm markers, including T (Brachyury). Instead, they begin to express a series of trophoblast markers, including HLA-G, demonstrate invasive properties that are independent of the continued presence of BMP4 in the medium, and, over time, produce extensive amounts of human chorionic gonadotropin, progesterone, placental growth factor, and placental lactogen. This process of differentiation is not dependent on conditioning of the medium by mouse embryonic fibroblasts and is accelerated in the presence of inhibitors of Activin and FGF2 signaling, which at day 2 provide colonies that are entirely KRT7 + and in which the majority of cells are transiently CDX2 + . Colonies grown on two chemically defined media, including the one in which BMP4 was reported to drive mesoderm formation, also differentiate at least partially to trophoblast in response to BMP4. The experiments demonstrate that the in vitro BMP4/hESC model is valid for studying the emergence and differentiation of trophoblasts.A popular model for examining the early commitment of cells to the trophoblast (TR) lineage is based on the initial observation of Xu et al. (1), who noted that a group of related factors in the TGF-β family, especially bone morphogenic protein 4 (BMP4), was capable of causing human ES cells (hESC) to differentiate efficiently to TRs. This differentiation occurred without extensive generation of mesoderm, endoderm, and ectoderm derivatives, as judged by microarray analysis of transcribed genes, although a low level of expression of genes characteristic of mesoderm and endoderm did occur. This model has become widely used (2-13) to study an aspect of early human development that is not easily addressed otherwise because of lack of access to human embryos. Over the course of these studies it was demonstrated that the key to obtaining differentiation primarily to TR rather than to other lineages when using BMP4 as the triggering agent was to exclude FGF2, a factor required for maintenance of hESC (14-17). When BMP4 is provided simultaneously with FGF2, the morphological transition of the cells is altered (10), and the colonies begin to form a range of mesoderm and endoderm derivatives in addition to TR (18). This effect is probably achieved by FGF2 signaling through the MEK/ERK pathway, thereby preserving NANOG expression (19,20). This body of work suggests that optimal differentiation to TR can be achieved best by maximizing BMP4 signaling while simultaneous...

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

Cited by 69 publications

References 105 publications

Heightened potency of human pluripotent stem cell lines created by transient BMP4 exposure

Heightened potency of human pluripotent stem cell lines created by transient BMP4 exposure

Small RNAs in early mammalian development: from gametes to gastrulation

Complete and unidirectional conversion of human embryonic stem cells to trophoblast by BMP4

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