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WIREs Dev Biol
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Properties of embryoid bodies

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Embryoid bodies (EBs) have been popular in vitro differentiation models for pluripotent stem cells for more than five decades. Initially, defined as aggregates formed by embryonal carcinoma cells, EBs gained more prominence after the derivation of karyotypically normal embryonic stem cells from early mouse blastocysts. In many cases, formation of EBs constitutes an important initial step in directed differentiation protocols aimed at generated specific cell types from undifferentiated stem cells. Indeed state‐of‐the‐art protocols for directed differentiation of cardiomyocytes still rely on this initial EB step. Analyses of spontaneous differentiation of embryonic stem cells in EBs have yielded important insights into the molecules that direct primitive endoderm differentiation and many of the lessons we have learned about the signals and transcription factors governing this differentiation event is owed to EB models, which later were extensively validated in studies of early mouse embryos. EBs show a degree of self‐organization that mimics some aspects of early embryonic development, but with important exceptions. Recent studies that employ modern signaling reporters and tracers of lineage commitment have revealed both the strengths and the weaknesses of EBs as a model of embryonic axis formation. In this review, we discuss the history, application, and future potential of EBs as an experimental model. WIREs Dev Biol 2017, 6:e259. doi: 10.1002/wdev.259

Outline of early‐ and late‐stage EB formation. Primitive endoderm is formed from the outermost cell layer around day 2 (D2) at which stage focal Wnt signaling is also observed. The Wnt response gradually expands to encompass the entire EB and concomitant with this Nodal‐response can be observed, initially also in discrete clusters before it expands to the entire central portion of the EB. At late stages, cavitation forms a yolk sac‐like structure and after day 7, some EBs can develop small outgrowths that have localized Wnt‐responsive cells at the tip. This is probably similar to what is observed in gastruloids, but in the gastruloids system it happens much more frequently. Light brown color in D7/>D7 indicates poorly defined signaling response. See main text for details.
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Schematic representation of mouse embryonic development from blastocyst to early‐streak stage. Signaling gradients of Bmp4, Wnt3, and Nodal and expression of the Wnt and Nodal antagonists Lefty1, Cerberus1 (Cer1), and Dickkopf1 (Dkk1), as well as expression of key transcription factors involved in epiblast/primitive endoderm fates are shown. See main text for details. AVE, anterior visceral endoderm; DE, definitive endoderm; DVA, distal visceral endoderm; Epi, epiblast; ExE, extraembryonic ectoderm; ICM, inner cell mass; PaE, parietal endoderm; Post. Epi/PS, posterior epiblast/primitive streak; PrE, primitive endoderm; TB, trophoblast cell; TE, trophectoblast; VE, visceral endoderm.
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Gene Expression and Transcriptional Hierarchies > Cellular Differentiation
Establishment of Spatial and Temporal Patterns > Cell Sorting and Boundary Formation
Signaling Pathways > Cell Fate Signaling