An ex vivo model for early anteroposterior organization during human development

The topic of these GEITP pages today is developmental biology. The body plan of mammalian embryos emerges through interactions of sequential cell-fate decisions and morphogenetic events — which have been difficult to observe in humans — until now. Human embryonic stem (hES) cells have opened up opportunities for studying early fate decisions, and have hinted at the existence of regulatory mechanisms that are specific to humans (i.e. not even seen in mouse embryo).

In contrast to the embryo in the intact animal, in which proportionate populations interact with one another to generate tissues and organs, differentiation in adherent culture is heterogeneous and (unfortunately) favors a limited number of cell types. Seeding hES cells on micropatterned surfaces yields coordinated patterns of gene expression — but, again, without the axial organization [i.e. axes that determine left-right, dorsal-ventral (back-front), anterior-posterior (head-tail]], which is characteristic of embryos.

When mouse ES cells are aggregated in suspension under defined conditions, however, they generate ‘gastruloids’, which are 3-dimensional ex vivo models of mammalian development that exhibit an embryo-like spatio-temporal organization of gene expression. Authors [see attached article] postulated that similar human gastruloids might be created from hES cells. When hES cells, in 2-dimensional culture — were treated with Chiron for one day — before seeding in low-adherence plates, they formed compact spherical aggregates within a few hours. [Chiron is an agonist of WNT (the combination of the names ‘wingless’ and ‘Int-1’, WNT-signaling pathways are a group of signal transduction pathways that can transfer signals into a cell through cell-surface receptors; WNTs are transcriptional coactivators of transcription factors belonging to the TCF/LEF family). These aggregates became asymmetrical and formed elongated gastrula-like structures — with maximal elongation at 72–96 h.

Authors identified these structures as gastruloids, i.e. “gastrula-like” (the gastrula develops from the hollow single-layered ball of cells called a ‘blastula’ — which is the product of repeated cell divisions, or cleavages, of a fertilized egg); the gastrula has eventually all three germinal layers of cells (epiderm, mesoderm, endoderm), from which the various organs are ultimately derived. Until now, such early stages of human embryo development (plus ethical and technical restrictions) have limited the feasibility of observing human gastrulation ex vivo.

Authors then used “spatial transcriptomics” to demonstrate that these gastruloids exhibit patterned gene expression; this included a signature of somitogenesis (process of formation of somites — which are bilaterally paired blocks of paraxial mesoderm that form along the anterior-posterior axis of developing embryo in segmented animals; in vertebrates, somites give rise to skeletal muscle, cartilage, tendons, endothelium, and dermis) — suggesting that these 72-h human gastruloids show some features of the “Carnegie-stage-9 human embryo.” This breakthrough study represents an experimentally tractable model system, by which one can now study human-specific regulatory processes that occur during axial organization in early development. 😊


Nature Jun 2020; 582: 410-415

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