A new era of stem cell and developmental biology: from blastoids to synthetic embryos and beyond

Abstract

Recent discoveries in stem cell and developmental biology have introduced a new era marked by the generation of in vitro models that recapitulate early mammalian development, providing unprecedented opportunities for extensive research in embryogenesis. Here, we present an overview of current techniques that model early mammalian embryogenesis, specifically noting models created from stem cells derived from two significant species: Homo sapiens, for its high relevance, and Mus musculus, a historically common and technically advanced model organism. We aim to provide a holistic understanding of these in vitro models by tracing the historical background of the progress made in stem cell biology and discussing the fundamental underlying principles. At each developmental stage, we present corresponding in vitro models that recapitulate the in vivo embryo and further discuss how these models may be used to model diseases. Through a discussion of these models as well as their potential applications and future challenges, we hope to demonstrate how these innovative advances in stem cell research may be further developed to actualize a model to be used in clinical practice.

Fig. 1. Timeline of seminal events in the fields of stem cell and developmental biology and in vivo embryogenesis including in vitro counterparts.

a Timeline of significant events in stem cell research facilitating the generation of synthetic embryos. b Illustration of early mammalian development in vivo (left), as well as the in vitro counterparts—naïve and primed ES cells—represented as cell states (right). Each developmental stage of the mammalian embryo is depicted from the fertilization of the egg (Day 0) to the implantation of the blastocyst (Day 9). Pre- (top) and post-implantation (bottom) stem cells derived in vitro are listed in the middle, as well as the original research in which they were discovered. The ESCs that correspond to the pre- and post-implantation states are naïve (top) and primed (bottom) ESCs, respectively, and the degrees of the states are represented on the right (ascending, more naïve; descending, more primed). Morphogens that regulate their states are written in between.

Fig. 2. Schematic representation of the in vivo embryo and corresponding in vitro models of the pre- and peri-implantation stages.

A depiction of the early developmental stages, spanning from the zygote phase (E0.5 of both mouse and human embryo) to the blastocyst stage (E5 and E7 of the mouse and human embryo, respectively), of mouse and human embryos are portrayed in the middle. In vitro models corresponding to the in vivo embryo of each developmental stage are illustrated on either side (top, mouse; bottom, human). Specific cells are color-coded throughout the figure (epiblast, green; hypoblast, pink; trophoblast, purple; ICM, yellow); the same color represents similar states at which they are in. Starting cells (C) of each model are noted adjacent to each illustration.

Fig. 3. Schematic representation of the in vivo embryo and corresponding in vitro models of the post-implantation stages.

In vivo developmental stages of the mouse and human embryos are depicted in the middle, from the process of gastrulation (E6.5 and E16 of the mouse and human embryo, respectively) to early organogenesis (E8.5 and E19 of the mouse and human embryo, respectively). In vitro models corresponding to the in vivo embryo of each developmental stage are illustrated on either side (top, mouse; bottom, human), as well as to note the original paper they were formed in. Specific tissues/organs are color-coded throughout the figure for both the embryos in gastrulation (mouse extraembryonic ectoderm, light purple; human extraembryonic ectoderm, dark purple; extraembryonic endoderm, pink; mesoderm, orange; endoderm, yellow; epiblast, blue) and those in early organogenesis (mouse extraembryonic ectoderm, light purple; extraembryonic endoderm, pink; brain, sky blue; spinal cord, turquoise; skin, dark navy; heart, red; notochord, dark red; somites, brown; presomitic mesoderm, dark orange; mesoderm, orange; gut and/or endoderm, yellow; neuromesodermal progenitors, green). Specific medium (M) or morphogens, including growth factors, cytokines, and inhibitors, used in the protocols for generating each in vitro model are listed adjacent to each gastruloid illustration.

Fig. 4. Congenital disease modeling via mouse and human synthetic embryos.

Cardiovascular defects (left), diseases associated with somitogenesis disruption (middle), and neurulation defects (right) may be modeled by current gastruloids. Appropriate gastrulation models are depicted in each category.