Opening the black box: Stem cell–based modeling of human post-implantation development

Abstract

Proper development of the human embryo following its implantation into the uterine wall is critical for the successful continuation of pregnancy. However, the complex cellular and molecular changes that occur during this post-implantation period of human development are not amenable to study in vivo. Recently, several new embryo-like human pluripotent stem cell (hPSC)–based platforms have emerged, which are beginning to illuminate the current black box state of early human post-implantation biology. In this review, we will discuss how these experimental models are carving a way for understanding novel molecular and cellular mechanisms during early human development.

High-resolution transcriptional and morphogenetic profiling of cells from micropatterned human embryonic stem cell gastruloid cultures

“…Human gastrulation remains unstudied due to ethical and experimental limitations. However, forward and reverse genetics studies in research animals provide deep insights into germ layer induction, patterning, and morphogenesis that inform hPSC-based experimental platforms to study aspects of human gastrulation (Rossant and Tam, 2016;Simunovic and Brivanlou, 2017;Shahbazi and Zernicka-Goetz, 2018;Taniguchi, Heemskerk and Gumucio, 2019). This work adopts and extends the micropatterned gastruloid system established by Brivanlou and collaborators (Warmflash et al, 2014).…”

Understanding the Mechanobiology of Early Mammalian Development through Bioengineered Models

“…To obviate these problems, many have turned toward self-organizing systems-based not on embryos but on pluripotent stem cells (PSCs) such as mESCs, human PSCs, or induced PSCs. These models recapitulate in vitro key features of in vivo development and include embryoid bodies, embryoids, two-dimensional (2D) and three-dimensional (3D) gastruloids (reviewed in Metzger et al, 2018;Shahbazi and Zernicka-Goetz, 2018;Simunovic and Brivanlou, 2017;Taniguchi et al, 2018) (Figure 2). Crucially, the use of PSCs allows for potentially highly quantitative and scalable approaches to developmental investigations.…”

“…For reasons partly deriving from current regulations restricting experimental work on living human embryos (Hurlbut et al, 2017), an analogous degree of knowledge does not yet exist for human development (Taniguchi et al, 2018). As such, while characterization efforts are underway (De Bakker et al, 2016;Behjati et al, 2018;Belle et al, 2017;Boroviak et al, 2018), our current understanding of the morphological features of early human development is still based on archival material of dedicated collections (De Bakker et al, 2016;Fujimoto, 2001;Gasser et al, 2014;Hertig et al, 1956), with insights into the signaling dependencies at play often relying on observations made on close primate species (see for example, Boroviak and Nichols, 2017;Nakamura et al, 2016).…”

“…Deflation experiments by Imuta et al (2014) have shown for example that the anisotropic forces exerted on the EPI by the expansion of the amniotic cavity drives the convergent-extension of cells during notochord morphogenesis ( Figure 1C). Additionally, mechanotransducing pathways have been posited to feed into the oscillatory networks driving somitogenesis (Hubaud et al, 2017) and mechanical cues may even guide the development of the amnion, in mouse as in human (Dobreva et al, 2018;Shao et al, 2017;Taniguchi et al, 2018). Even more interestingly, mechanosensitive gene expression has been documented in various developmental models (Brunet et al, 2013) as well as in sea anemones where prolonged embryo compression licenses ectopic expression of the gastrulation marker T/Brachyury (T/Bra) (Pukhlyakova et al, 2018).…”

Bioengineered microenvironment to culture early embryos

“…Addition to the above mentioned limitations, in vitro cultured embryos cannot match the size and the number of cells of natural embryos. 17,109 Bioengineered microenvironments including biomaterials and stimuli are expected to be adjusted to better mimic the in vivo microenvironments for the optimal development of the embryo in vitro.…”