Sculpting with stem cells: how models of embryo development take shape

Abstract

During embryogenesis, organisms acquire their shape given boundary conditions that impose geometrical, mechanical and biochemical constraints. A detailed integrative understanding how these morphogenetic information modules pattern and shape the mammalian embryo is still lacking, mostly owing to the inaccessibility of the embryo in vivo for direct observation and manipulation. These impediments are circumvented by the developmental engineering of embryo-like structures (stembryos) from pluripotent stem cells that are easy to access, track, manipulate and scale. Here, we explain how unlocking distinct levels of embryo-like architecture through controlled modulations of the cellular environment enables the identification of minimal sets of mechanical and biochemical inputs necessary to pattern and shape the mammalian embryo. We detail how this can be complemented with precise measurements and manipulations of tissue biochemistry, mechanics and geometry across spatial and temporal scales to provide insights into the mechanochemical feedback loops governing embryo morphogenesis. Finally, we discuss how, even in the absence of active manipulations, stembryos display intrinsic phenotypic variability that can be leveraged to define the constraints that ensure reproducible morphogenesis in vivo.

Sequential And Directional Insulation By Conserved CTCF Sites Underlies The Hox Timer In Pseudo-Embryos

“…Here we address this question by using pseudo-embryos referred to as gastruloids (Turner et al, 2017) derived from an aggregate of ES cells cultivated in vitro for several days. After activating Wnt signaling for 24h, such ‘stembryos’ (Veenvliet et al, 2021) start to elongate a protrusion that resembles the outgrowth and progression of the tail bud and where the Hox timer is implemented (Beccari et al, 2018). We looked at various indicators of transcription, at the dynamic of cohesin recruitment and accumulation and at the changing architecture of the HoxD locus in parallel with its activation, and show that the Hox timer starts with a Wnt -dependent activation of the CTCF-free part of the cluster, which triggers an increased loading of cohesin complexes over this transcribed region.…”

A stem cell zoo uncovers intracellular scaling of developmental tempo across mammals

“…With the recent expansion of the PSC technologies, we can now extend our knowledge of development outside of the classical mouse and human models. In vitro differentiation of PSCs from different mammalian species can be used to recapitulate key features of development and study them under similar experimental conditions 14 . For example, comparisons of human and primate PSC-derived brain models have helped reveal unique properties of human brain development 15,16 .…”

Succinate as a New Actor in Pluripotency and Early Development?

“…Recent literature shows that in vivo, a controlled balance for succinate is required for the establishment of a healthy pregnancy and is overall favorable for the proper pre-implantation development. Further metabolomic characterizations of the developing embryo could reinforce the importance of succinate and maybe its receptor SUCNR1 in development, especially with the use of state-of-the-art 3D models (reviewed in [ 116 , 117 ]). Along with these, in vitro models of early development and stem cell states transitions also offer insights into the deep impact of the metabolite on growth and differentiation capacities.…”