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New Study Describes the Formation of Embryo-like Entities from Pluripotent Stem Cells

Review of “Construction of a mammalian embryo model from stem cells organized by a morphogen signalling centre” from Nature Communications by Stuart P. Atkinson

Recent research from the laboratory of Christine Thisse (University of Virginia, Charlottesville, VA, USA) demonstrated how experimentally generated and opposing gradients of bone morphogenetic protein and Nodal, which induce the expression of zygotic Wnt, prompted the formation of a complete zebrafish embryonic axis in either naive pluripotent cells of animal pole explants [1, 2] or aggregates of dissociated and reassociated animal pole blastomeres [3].

The Thisse lab next sought to employ this strategy to generate differentiated embryonic structures in vitro from pluripotent stem cells, and now, Xu et al. report that an engineered and localized morphogen signaling center within an aggregate of mouse embryonic stem cells (ESCs) can support the development of embryo-like entities or “embryoids” that exhibit extensive development of germ layer derivatives [4].

The authors demonstrated that an aggregate of mouse ESCs expressing WNT3 and NODAL, which functioned as a signaling center that triggered the expression of downstream factors that induce and execute developmental programs, could instruct another merged aggregate of untreated ESCs to form embryoids by inducing and controlling patterning and morphogenesis. Excitingly, a thoroughly optimized protocol formed embryoids that elongated, underwent gastrulation, and displayed signs of the differentiation of germ layer derivatives. Embryoids also became patterned along their anteroposterior and dorsoventral axes, thereby displaying similarities to neurula-stage mouse embryos.

The authors noted early embryoid developmental events comparable to the formation of the primitive endodermal cell population of mouse blastula stage embryos. Later stages of embryoid formation coincided with the formation of an endoderm-like epithelium expressing markers of different primitive gut-like tube regions, which then folded into foregut and hindgut segments and formed various regions of the gut tube epithelium, including yolk stalk- and yolk sac-like structures.

Embryoids also exhibited signs of mesodermal differentiation, which included the formation of a notochord-like structure extending along the posterior-anterior axis underneath the neural plate and above the endoderm epithelium. The team identified segmented paraxial mesoderm and intermediate mesoderm domains lateral to the axial mesoderm, which included cardiac tissue, primitive erythrocytes, and blood vessels networks.

The authors also noted the presence of an ectodermal layer that differentiated into a neural plate-like structure comparable to the mouse embryo neuroepithelium, which folded and closed into a neural tube in a subset of embryoids. The embryoids developed from the posterior midbrain to the tip of the caudal region, and the neural plate exhibited both anteroposterior and dorsoventral patterning.

While the embryoid model described represents a considerable step forward in reproducing mammalian embryonic development in vitro, they remain an incomplete model due to a lack of the anterior-most brain domains, a lack of a reproducible topographic organization in the forebrain, the random nature of dorsal-ventral patterning, and the maintenance of embryoid culture under minimal conditions.

For more on the in vitro formation of embryo models from pluripotent stem cells, stay tuned to the Stem Cells Portal!


  1. Xu P-F, Houssin N, Ferri-Lagneau KF, et al., Construction of a Vertebrate Embryo from Two Opposing Morphogen Gradients. Science 2014;344:87.
  2. Thisse B and Thisse C, Formation of the vertebrate embryo: Moving beyond the Spemann organizer. Seminars in Cell & Developmental Biology 2015;42:94-102.
  3. de Olivera-Melo M, Xu P-F, Houssin N, et al., Generation of Ectopic Morphogen Gradients in the Zebrafish Blastula, in Morphogen Gradients: Methods and Protocols, J. Dubrulle, Editor. 2018, Springer New York: New York, NY. p. 125-141.
  4. Xu P-F, Borges RM, Fillatre J, et al., Construction of a mammalian embryo model from stem cells organized by a morphogen signalling centre. Nature Communications 2021;12:3277.