Abstract:Highlights d Stem cells generate mouse-embryo-like structures with improved potential d These structures undertake anterior visceral endoderm formation and gastrulation d Single-cell sequencing shows improved resemblance to mouse embryo
“…In the last section, we describe the first results of using synthetic biology in embryo models and speculate on how other studies in embryo models could be carried out with the tools and approaches of synthetic biology ( Figure 5 ). Figure 5 Application of synthetic biology tools and approaches to embryo models (A) Increasing developmental potential of embryo models: transient overexpression of Gata4 transcription factor enabled generation of a more developmentally potent mouse embryo model ( Amadei et al., 2021 ). (B) Potential application of synthetic rescue of a developmental mutation in embryo model.…”
Section: Main Textmentioning
confidence: 99%
“… (A) Increasing developmental potential of embryo models: transient overexpression of Gata4 transcription factor enabled generation of a more developmentally potent mouse embryo model ( Amadei et al., 2021 ). …”
Section: Main Textmentioning
confidence: 99%
“…For construction of better embryo models, simple artificial genetic circuits have been used in a recent study by the Zernicka-Goetz group ( Amadei et al., 2021 ) ( Figure 5 A). The embryo model that was improved with genetic engineering is called ETX, a model that partially recapitulates mouse development by combining embryonic stem cells (ESCs), trophoblast stem cells (TS), and extra-embryonic endoderm (XEN) stem cells ( Sozen et al., 2018 ).…”
Recently, developmental systems are investigated with increasing technological power. Still, open questions remain, especially concerning self-organization capacity and its control. Here, we present three areas where synthetic biology tools are used in top-down and bottom-up approaches for studying and constructing developmental systems. First, we discuss how synthetic biology tools can improve stem cell-based organoid models. Second, we discuss recent studies employing user-defined perturbations to study embryonic patterning in model species. Third, we present ''toy models'' of patterning and morphogenesis using synthetic genetic circuits in non-developmental systems. Finally, we discuss how these tools and approaches can specifically benefit the field of embryo models.
“…In the last section, we describe the first results of using synthetic biology in embryo models and speculate on how other studies in embryo models could be carried out with the tools and approaches of synthetic biology ( Figure 5 ). Figure 5 Application of synthetic biology tools and approaches to embryo models (A) Increasing developmental potential of embryo models: transient overexpression of Gata4 transcription factor enabled generation of a more developmentally potent mouse embryo model ( Amadei et al., 2021 ). (B) Potential application of synthetic rescue of a developmental mutation in embryo model.…”
Section: Main Textmentioning
confidence: 99%
“… (A) Increasing developmental potential of embryo models: transient overexpression of Gata4 transcription factor enabled generation of a more developmentally potent mouse embryo model ( Amadei et al., 2021 ). …”
Section: Main Textmentioning
confidence: 99%
“…For construction of better embryo models, simple artificial genetic circuits have been used in a recent study by the Zernicka-Goetz group ( Amadei et al., 2021 ) ( Figure 5 A). The embryo model that was improved with genetic engineering is called ETX, a model that partially recapitulates mouse development by combining embryonic stem cells (ESCs), trophoblast stem cells (TS), and extra-embryonic endoderm (XEN) stem cells ( Sozen et al., 2018 ).…”
Recently, developmental systems are investigated with increasing technological power. Still, open questions remain, especially concerning self-organization capacity and its control. Here, we present three areas where synthetic biology tools are used in top-down and bottom-up approaches for studying and constructing developmental systems. First, we discuss how synthetic biology tools can improve stem cell-based organoid models. Second, we discuss recent studies employing user-defined perturbations to study embryonic patterning in model species. Third, we present ''toy models'' of patterning and morphogenesis using synthetic genetic circuits in non-developmental systems. Finally, we discuss how these tools and approaches can specifically benefit the field of embryo models.
“…(2019) ET embryoid mouse mESC + mTSC AP axis formation; primitive streak and mesoderm formation; PGC specification; EPI and trophoblast compartment interaction Harrison et al. (2017) ETX embryoid mouse mESC + mTSC + mXEN; Gata6-pulsed mESC + mTSC cavity formation; AP axis formation; primitive streak formation; EMT; mesoderm and endoderm formation; AVE migration; EPI, trophoblast and extraembryonic endoderm compartment interaction; PGC specification; initiation of decidualization Sozen et al (2018) Zhang et al (2019) Amadei et al (2021) EB mouse, human mESC, hESC germ layer formation Martin and Evans (1975) Martin et al. (1977) Itskovitz-Eldor et al (2000) polarizing EB/3D gastruloid mouse mESC, mEC primitive streak gene expression; AP, DV, and LR axis patterning; spatial gene expression of germ layers and patterning (e.g., Hox genes) ten Berge et al.…”
Section: Main Textmentioning
confidence: 99%
“…Indeed, these Gata6/Nanog double-positive cells were shown to be able to differentiate into an ESC or a XEN-like fate upon release from Gata6-overexpression, which was also exploited in a cell-based model of the ICM, termed ICM organoids ( Mathew et al., 2019 ). Very recently, Gata6-pulsed mESCs were also used to build ETX embryoids, and were shown to be superior sources for EPI and PE-derived lineages, compared with using a mix of ESCs and conventional XEN cells as building blocks ( Amadei et al, 2021 ).…”
Detailed studies of the embryo allow an increasingly mechanistic understanding of development, which has proved of profound relevance to human disease. The last decade has seen
in vitro
cultured stem cell-based models of embryo development flourish, which provide an alternative to the embryo for accessible experimentation. However, the usefulness of any stem cell-based embryo model will be determined by how accurately it reflects
in vivo
embryonic development, and/or the extent to which it facilitates new discoveries. Stringent benchmarking of embryo models is thus an important consideration for this growing field. Here we provide an overview of means to evaluate both the properties of stem cells, the building blocks of most embryo models, as well as the usefulness of current and future
in vitro
embryo models.
Combining high‐throughput generation and high‐content imaging of embryo models will enable large‐scale screening assays in the fields of (embryo) toxicity, drug development, embryogenesis, and reproductive medicine. This study shows the continuous culture and in situ (i.e., in microwell) imaging‐based readout of a 3D stem cell‐based model of peri‐implantation epiblast (Epi)/extraembryonic endoderm (XEn) development with an expanded pro‐amniotic cavity (PAC) (E3.5 E5.5), namely XEn/EPiCs. Automated image analysis and supervised machine learning permit the identification of embryonic morphogenesis, tissue compartmentalization, cell differentiation, and consecutive classification. Screens with signaling pathway modulators at different time windows provide spatiotemporal information on their phenotypic effect on developmental processes leading to the formation of XEn/EPiCs. Exposure of the biological model in the microwell platform to pathway modulators at two time windows, namely 0–72 h and 48–120 h, show that Wnt and Fgf/MAPK pathway modulators affect Epi differentiation and its polarization, while modulation of BMP and Tgfβ/Nodal pathway affects XEn specification and epithelialization. Further, their collective role is identified in the timing of the formation and expansion of PAC. The newly developed, scalable culture and analysis platform, thereby, provides a unique opportunity to quantitatively and systematically study effects of pathway modulators on early embryonic development.
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