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

Wisconsin National Primate Research Center, University of Wisconsin, 1223 Capitol Court, Madison, Wisconsin 53715-1299, USA.
Endocrine reviews (Impact Factor: 21.06). 04/2009; 30(3):228-40. DOI: 10.1210/er.2009-0001
Source: PubMed


The placenta is an ephemeral organ containing diverse populations of trophoblasts that are all derived from the embryonic trophectoderm but have morphological, functional, and molecular diversity within and across species. In hemochorial placentation, these cells play especially important roles, interfacing with and modifying the cells of the maternal decidua. Within the rapidly growing placenta, it has been shown that there are trophoblast stem cells well characterized in the mouse and postulated but not well understood in primates. This review will discuss the characteristics of candidates for human and nonhuman primate trophoblast stem cells, present the diverse methods of their generation, and propose future prospects for experimental systems in which they can shed light on developmental and pathophysiological processes in human pregnancy.

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    • "These are similar culture conditions as required for the derivation and propagation of mTS lines (Yamanaka et al., 2006) and mEpiSC lines (Brons et al., 2007; Tesar et al., 2007). The derivation of stable human XEN and TS lines has not yet been reported either after single blastomere plating or after blastocyst plating (Douglas et al., 2009). "
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    ABSTRACT: During human pre-implantation development the totipotent zygote divides and undergoes a number of changes that lead to the first lineage differentiation in the blastocyst displaying trophectoderm and inner cell mass on day 5. The trophectoderm is a differentiated epithelium needed for implantation and the inner cell mass (ICM) forms the embryo proper and serves as a source for pluripotent embryonic stem cells. The blastocyst implants around day 7. The second lineage differentiation occurs in the ICM after implantation resulting in specification of primitive endoderm and epiblast. Knowledge on human pre-implantation development is limited due to ethical and legal restrictions on embryo research and scarcity of materials. Studies in the human are mainly descriptive and lack functional evidence. Most information on embryo development is obtained from animal models and embryonic stem cell cultures and should be extrapolated with caution. This paper reviews totipotency and the molecular determinants and pathways involved in lineage segregation in the human embryo, as well as the role of embryonic genome activation, cell cycle features and epigenetic modifications.
    Molecular Human Reproduction 04/2014; 20(7). DOI:10.1093/molehr/gau027 · 3.75 Impact Factor
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    • "While human term placentas are easily obtained, they do not provide invasive EVT. In contrast, first trimester placental tissue will form EVT in vitro, but is not widely available, and cannot be maintained long term in culture [11] [12]. Immortalized cell lines with EVT properties such as HTR8 (HTR-8/SVneo) [13], TEV-1 [14], Swan-71 [15], TCL1 [16] and SGHPL-4 [17] are widely used, but these cells are already committed to the EVT lineage and preclude investigation of their origins [18] [19]. "
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    ABSTRACT: Introduction: Preeclampsia and other placental pathologies are characterized by a lack of spiral artery remodeling associated with insufficient invasion by extravillous trophoblast cells (EVT). Because trophoblast invasion occurs in early pregnancy when access to human placental tissue is limited, there is a need for model systems for the study of trophoblast differentiation and invasion. Human embryonic stem cells (hESC) treated with BMP4- differentiate to trophoblast, and express HLA-G, a marker of EVT. The goals of the present study were to further characterize the HLA-G(+) cells derived from BMP4-treated hESC, and determine their suitability as a model. Methods: HESC were treated with BMP4 under 4% or 20% oxygen and tested in Matrigel invasion chambers. Both BMP4-treated hESC and primary human placental cells were separated into HLA-G(+) and HLA-G(-)/TACSTD2(+) populations with immunomagnetic beads and expression profiles analyzed by microarray. Results: There was a 10-fold increase in invasion when hESC were BMP4-treated. There was also an independent, stimulatory effect of oxygen on this process. Invasive cells expressed trophoblast marker KRT7, and the majority were also HLA-G(+). Gene expression profiles revealed that HLA-G(+), BMP4-treated hESC were similar to, but distinct from, HLA-G(+) cells isolated from first trimester placentas. Whereas HLA-G(+) and HLA-G(-) cells from first trimester placentas had highly divergent gene expression profiles, HLA-G(+) and HLA-G(-) cells from BMP4-treated hESC had somewhat similar profiles, and both expressed genes characteristic of early trophoblast development. Conclusions: We conclude that hESC treated with BMP4 provide a model for studying transition to the EVT lineage.
    Placenta 04/2013; 34(7). DOI:10.1016/j.placenta.2013.03.016 · 2.71 Impact Factor
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    • "The derivation of TB from embryoid bodies assembled from hESC was described by Gerami-Naini et al. ( 2004) and has been reviewed several times recently (Golos et al. 2006, 2010; Douglas et al. 2009). The approach has been to disperse the cells into clumps, which are then cultured under conditions where they cannot re-adhere. "
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    ABSTRACT: This review focuses on a now well-established model for generating cells of the trophoblast (TB) lineage by treating human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) with the growth factor BMP4. We first discuss the opposing roles of FGF2 and BMP4 in directing TB formation and the need to exclude the former from the growth medium to minimize the co-induction of mesoderm and endoderm. Under these conditions, there is up-regulation of several transcription factors implicated in TB lineage emergence within 3 h of BMP4 exposure and, over a period of days and especially under a high O(2) gas atmosphere, gradual appearance of cell types carrying markers for more differentiated TB cell types, including extravillous TB and syncytioTB. We describe the potential value of including low molecular weight pharmaceutical agents that block activin A (INHBA) and FGF2 signaling to support BMP4-directed differentiation. We contend that the weight of available evidence supports the contention that BMP4 converts human ESC and iPSC of the so-called epiblast type unidirectionally to TB. We also consider the argument that BMP4 treatment of human ESC in the absence of exogenous FGF2 leads only to the emergence of mesoderm derivatives to be seriously flawed. Instead, we propose that, when signaling networks supporting pluripotency ESC or iPSC become unsustainable and when specification towards extra-embryonic mesoderm and endoderm are rendered inoperative, TB emerges as a major default state to pluripotency.
    Cell and Tissue Research 03/2012; 349(3):809-24. DOI:10.1007/s00441-012-1371-2 · 3.57 Impact Factor
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