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Stem-Cell-Based Embryo Models for Fundamental Research and Translation

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Stem-Cell-Based Embryo Models for Fundamental Research and Translation REVIEW ARTICLE https://doi.org/10.1038/s41563-020-00829-9 Stem-cell-based embryo models for fundamental research and translation Jianping Fu 1,2,3 ✉ , Aryeh Warmflash 4,5 ✉ and Matthias P. Lutolf 6,7 ✉ Despite its importance, understanding the early phases of human development has been limited by availability of human sam- ples. The recent emergence of stem-cell-derived embryo models, a new field aiming to use stem cells to construct in vitro models to recapitulate snapshots of the development of the mammalian conceptus, opens up exciting opportunities to promote fundamental understanding of human development and advance reproductive and regenerative medicine. This Review provides a summary of the current knowledge of early mammalian development, using mouse and human conceptuses as models, and emphasizes their similarities and critical differences. We then highlight existing embryo models that mimic different aspects of mouse and human development. We further discuss bioengineering tools used for controlling multicellular interactions and self-organization critical for the development of these models. We conclude with a discussion of the important next steps and exciting future opportunities of stem-cell-derived embryo models for fundamental discovery and translation. he development of a multicellular organism from a single notable progress in studying non-human primate (NHP) monkey fertilized egg is a brilliant triumph of evolution that has fas- embryos10–12, whose developments are similar to humans. However, Tcinated generations of scientists (Box 1). Understanding our NHP monkey models remain costly, are difficult to modify geneti- own development is of particular fundamental and practical inter- cally, and have their own ethical challenges. est; however, it poses a unique set of technical and ethical challenges. Recent advances in mammalian embryology, stem cell biol- Our current knowledge of embryonic development is derived from ogy, organoid technology, and bioengineering have contributed a number of animal species, chosen because they are convenient to to a considerable interest in the development of multicellular study and amenable to experimental manipulation or genetic analy- systems based on emergent self-organization and tissue pattern- sis1. These studies have revealed developmental principles (Box 2), ing. Importantly, different models of the mammalian conceptus and signalling and transcriptional networks that underlie cell fate have been developed using mouse and human stem cells13–30. This patterning and tissue morphogenesis. In particular, most of our emerging field aims to use stem cell cultures to create organized knowledge of mammalian development derives from the mouse embryo-like structures (or embryoids), whose development and model. However, it is becoming evident that there are morphologi- architecture bear remarkable similarities to their in vivo coun- cal and genetic differences between mice and humans that make terparts. Embryoids are distinct from organoids, as organoids cross-species comparisons problematic2. are organized multicellular structures that mimic the develop- Knowledge of human embryogenesis, which is critical for ment, regeneration and homeostasis of a single tissue or organ. assisted reproductive technologies and prevention of pregnancy In contrast, embryoids aim to model integrated development of loss, birth defects and teratogenesis (Box 3), should ideally be the entire conceptus or a considerable portion thereof. In gen- learned from studying the human embryo per se; however, such eral, embryoids have a more reproducible cellular organization studies have been challenging due to limited access to and bioethical and architecture than organoids, as bioengineering approaches constraints on human embryo specimens. Excess pre-implantation are commonly deployed to guide their development and culture human embryos generated in in vitro fertilization (IVF) clinics are time is limited to a few days. In addition, the stem cells used in available for research3,4; however, once a human embryo implants embryoids have been well established and their cultures are usu- into the uterus, subsequent development is hidden from direct ally robust. This Review discusses the developmental principles observation. Recent progress in prolonged in vitro culture of IVF manifested in the development of embryoids and their appli- human embryos has opened the door for genetic and molecu- cations for advancing human embryology (particularly at the lar studies of human embryos directly5–7. However, international post-implantation stages) and reproductive and regenerative guidelines prohibit in vitro culture of human embryos beyond 14 medicine. Bioengineering tools used for controlling multicellular days post-fertilization (embryonic day 14, E14.0) or reaching the interactions and self-organization critical for embryoid develop- onset of primitive streak (PS) development (‘the 14-day rule’)8,9, ment are highlighted. We conclude with a discussion of impor- which marks the outset of gastrulation. The bioethical regulation of tant next steps to leverage advanced bioengineering controls of human embryo culture has limited studies of IVF human embryos multicellular interactions to promote the continuous, progressive for understanding post-implantation human development. There is development of this exciting nascent field. 1Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, USA. 2Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. 3Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA. 4Department of Biosciences, Rice University, Houston, TX, USA. 5Department of Bioengineering, Rice University, Houston, TX, USA. 6Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences and School of Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 7Institute of Chemical Sciences and Engineering, School of Basic Science, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. ✉e-mail: [email protected]; [email protected]; [email protected] 132 NATURE MATERIALS | VOL 20 | FebruarY 2021 | 132–144 | www.nature.com/naturematerials NATURE MATERIALS REVIEW ARTICLE Box 1 | Glossary Box 2 | Classic developmental concepts and principles Conceptus. Te products of conception at all stages of develop- Developmental potency. Developmental potency describes the ment from zygote to birth. Tese include the embryo proper, the ability of a cell in the embryo to diferentiate into other cell types. fetus, the placenta and all extraembryonic membranes. Te term Tere is a continuum of developmental potency following pro- ‘embryo proper’ refers to those parts of the conceptus that will gressive development of the embryo, from totipotency, pluripo- form the new body and excludes extraembryonic tissues. Ofen, tency, multipotency, oligopotency and fnally unipotency. the terms ‘embryo’ and ‘conceptus’ are used interchangeably. Pattern formation. Pattern formation is the process by which Pre-implantation development. Te frst few days of initially equivalent cells in a developing tissue acquire identities development, from fertilization to implantation, during which that lead to a well-ordered spatial pattern of cell activities. Pattern the conceptus travels down the oviduct toward the uterus. It formation can involve positional information or cell sorting (see encompasses the frst 7–9 days afer fertilization in humans. below). Morula. Te very early stage in a conceptus when cleavage has Positional information. Te concept of positional information resulted in a solid ball of cells. proposes that cells in a developing tissue acquire positional Implantation. Te process of attachment and invasion of the values as in a coordinate system, which they interpret by conceptus to the uterine tissues that occurs around day 7–9 developing in particular ways to give rise to spatial patterns. afer fertilization in humans. Implantation establishes the fetal– Positional information ofen involves difusion of morphogens, maternal interface leading to later placental development. leading to signalling gradients and diferential gene expression in a morphogen concentration-dependent manner. A key feature Blastula and blastocyst. Te stage of the conceptus prior to of positional information being the basis for pattern formation is implantation is termed blastula. At this stage, the conceptus is that there is no pre-pattern in the developing tissue. called a blastocyst. Cell sorting. Pattern formation in a developing tissue can initiate Peri-implantation development. Te development of the from the specifcation of diferent cell types in the tissue in a conceptus in the uterine tissues prior to gastrulation. salt-and-pepper fashion, which is followed by sorting of diferent Gastrula and gastrulation. Gastrulation describes the process cell types into distinct domains from where diferent tissues are by which the three defnitive germ layers of the embryonic formed. Cell sorting involves a morphogenetic process during compartment of the conceptus are formed. Gastrulation begins which individual cells exchange neighbours, increasing the around day 14 in humans. Te gastrulation stage conceptus is number of homotypic contacts and decreasing the number of termed gastrula. heterotypic contacts. Primitive streak. Te embryonic structure that breaks radial Symmetry breaking. Symmetry breaking is the process
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