Examining the State of the Science of Mammalian Embryo Model Systems Proceedings of a Workshop (2020) / Chapter Skim
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2 Mammalian Embryo Research and Pluripotent Stem Cells
2 Mammalian Embryo Research and Pluripotent Stem Cells
Pages 11-28
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From page 11... ...
• Insulin growth factor promotes the proliferation of the plu ripotent epiblast in embryonic stem cells and, together with Nodal Growth Differentiation Factor (Nodal) /Activin, sup ports the derivation and maintenance of embryonic stem cells and induced pluripotent stem cells.
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From page 12... ...
(Cook-Andersen) The first session of the workshop focused on mammalian embryo research and pluripotent stem cells with the aim of exploring the characteristics of mammalian embryo model systems and the potential benefits and limitations to using these models for studying human embryonic development.
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culture conditions. In her presentation, Niakan highlighted distinct expression dynamics in human versus mouse embryos, explained why human pluripotent stem cell culture conditions need to be improved, and described how genome editing can contribute to the understanding of early human development.
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Distinct Expression Dynamics in Human Versus Mouse Embryos To better understand the mechanisms of lineage specification, Niakan's laboratory performed single-cell RNA sequencing to catalog which genes are expressed throughout the various pre-implantation stages of human development and then compared this list of genes with the corresponding one for the mouse, which remains the most important model organism for comparative analysis. A comparison of these transcriptome analyses for the two species revealed striking differences in the temporal gene expression patterns between the homologous or potentially orthologous genes in the two species (Blakeley et al., 2015)
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From page 15... ...
However, there are important justifications for continued research into how pluripotent epiblast cells form and how to refine hESC culture conditions using actual human embryos, she continued. Decades of work with iPSCs and ESCs have been valuable, but pluripotent stem cell culture conditions need to be improved to more closely approximate the processes of normal embryonic development.
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They found that irrespective of the culture conditions, established hESCs are somewhat transcrip 2NANOG is a transcription factor that helps embryonic stem cells maintain pluripotency by suppressing cell determination factors.
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This suggests that further refinements of human pluripotent stem cell culture conditions are needed and that a basic understanding of how the embryonic epiblast develops in human embryos may provide key insights into how to make further improvements. Based on this work, Niakan said she believes that FGF and Nodal signaling may differ in how they function in mouse and human preimplantation development.
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BUILDING EMBRYO MODELS TO STUDY HUMAN DEVELOPMENT Magdalena Zernicka-Goetz, a professor of mammalian development and stem cell biology at the University of Cambridge and the Bren Professor of Biology and Biological Engineering at the California Institute of Technology, described her laboratory's work on early post-implantation human embryo development that led to the development of synthetic 3D stem cell models. She cited two reasons for studying early human development: (1)
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From page 19... ...
to develop a system to culture human embryos beyond day 7 in vitro that is as similar as possible to human development in vivo and (2) to develop a system to model human development with stem cells.
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Developmental Consequences of Specific Aneuploidies The culture conditions developed to study normal human embryo development can also be used to look at aneuploid embryos and identify the developmental consequences of specific aneuploidies, Zernicka-Goetz said. She maintained that this stem cell–based system has great potential to further our understanding of how genes on specific chromosomes contribute to the phenotype and behavior of trophectoderm, epiblast, and hypoblast.
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Their research aim was to inform the mechanistic understanding of development by reconstructing mammalian embryos using the building blocks of stem cells for three distinct tissues: ESCs from epiblast, extraembryonic endoderm (XEN) cells from primitive endoderm, and trophoblast stem cells (TSCs)
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CLINICAL PERSPECTIVE ON PRE-IMPLANTATION HUMAN EMBRYO DEVELOPMENT Heidi Cook-Andersen, an assistant professor of reproductive medicine at the University of California, San Diego, offered a clinical perspective on how studying pre-implantation human embryo development can elucidate inefficiencies in human reproduction in order to improve treatments for infertility and assisted reproductive technology. Her laboratory is exploring developmental benchmarks in embryos that can be reproduced and studied in model systems to improve IVF and reproductive treatments.
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Exploring the Molecular Basis for Successful Implantation of the Human Embryo Cook-Andersen and her colleagues are investigating high rates of implantation failure in human embryos in order to understand ultimately what is required at the molecular level for successful implantation. Decades of studies in IVF clinics have strongly established that embryos with "good morphology" have much lower implantation failure rates and much higher live birth rates than embryos with poor morphologies (Irani et al., 2017; Nazem et al., 2019)
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By directly comparing their findings in blastocysts of good and poor morphology, this approach provides the opportunity to develop prioritized gene lists and identify the molecular pathways important for successful human embryo implantation and the defects in these pathways that might contribute to the high rates of implantation failure seen in humans. Early findings suggest primitive endoderm development in pre-implantation embryos may play an important role in the success or failure of implantation, at least in the IVF setting, she said.
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Naïve and Expanded-Potential Stem Cells Panelists were asked for clarification about the definitions of naïve and expanded-potential stem cells. Earlier studies showed that ESCs can contribute to extraembryonic mesoderm, but more recent studies indicate that there is variability between naïve and expanded-potential cells.
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A workshop participant suggested that single-cell databases for nonhuman primates could be analyzed for evidence of evolutionary changes that might explain the role of primitive endoderm in implantation failure in humans. Embryo-to-Embryo Variability in Modeling Human Development The question of how to account for embryo-to-embryo genetic and epigenetic variability in humans when translating work done using mouse models to human models was raised by a workshop participant.
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Future Research Directions Panelists were asked to reflect on the research questions that emerged from the first session. Rossant commented that using stem cells to make embryo models will require answering two fundamental questions: (1)
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Furthermore, she suggested that new genome editing technologies and methods for protein depletion and manipulating gene function will contribute to identifying molecular mechanisms across species and improving stem cell biology techniques. However, she cautioned against underestimating the value of mouse and nonhuman primate models.
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