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
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.
Available from: Maria Krivega
- "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.
Available from: Muriel Bardor
- "For example, leukemic inhibitor factor is required for mESC culture but not for hESC (Ginis et al., 2004). In addition, trophoblast lineage cannot be derived from mESC differentiation but can be obtained from hESC differentiation (Douglas et al., 2009). Here, we investigated the effect that O-GlcNAc has on the maintenance of pluripotency and directing differentiation of both hESC and iPSC. "
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ABSTRACT: O-linked-N-acetylglucosamine (O-GlcNAc), a post translational modification, has emerged as an important cue in controlling key cell mechanisms. Here, we investigate O-GlcNAc's role in the maintenance and differentiation of human pluripotent stem cells (hPSC). We reveal that protein expression of O-GlcNAc transferase and hydrolase both decreases during hPSC differentiation. Upregulating O-GlcNAc with O-GlcNAc hydrolase inhibitors has no significant effect on either the maintenance of pluripotency in hPSC culture, or the loss of pluripotency in differentiating hPSC. However, in spontaneously differentiating hPSC, excess O-GlcNAc alters the expression of specific lineage markers: decrease of ectoderm markers (PAX6 by 53-88%, MSX1 by 26-49%) and increase of adipose-related mesoderm markers (PPARγ by 28-100%, C/EBPα by 46-135%). All other lineage markers tested (cardiac, visceral-endoderm, trophectoderm) remain minimally affected by upregulated O-GlcNAc. Interestingly, we also show that excess O-GlcNAc triggers a feedback mechanism that increases O-GlcNAc hydrolase expression by 29-91%. To the best of our knowledge, this is the first report demonstrating that excess O-GlcNAc does not affect hPSC pluripotency in undifferentiated maintenance cultures; instead, it restricts the hPSC differentiation towards specific cell lineages. These data will be useful for developing targeted differentiation protocols and aid in understanding the effects of O-GlcNAc on hPSC differentiation.
Available from: Toshihiko Ezashi
- "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  . Immortalized cell lines with EVT properties such as HTR8 (HTR-8/SVneo) , TEV-1 , Swan-71 , TCL1  and SGHPL-4  are widely used, but these cells are already committed to the EVT lineage and preclude investigation of their origins  . "
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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.
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.
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.
We conclude that hESC treated with BMP4 provide a model for studying transition to the EVT lineage.
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