<i>In vitro</i>endoderm emergence and self-organisation in the absence of extraembryonic tissues and embryonic architecture

Vianello, Stefano

doi:10.1101/2020.06.07.138883

Cited by 36 publications

(53 citation statements)

References 90 publications

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“…However Bra/T + cells do not ingress from an epithelial layer, which appears to be nonexistent at early stages, instead they emerge at seemingly random positions and thereupon arrange into a pole without underlying directional preference, as mentioned above. Likewise, recent studies on endodermal cells in gastruloids have shown that they are specified without the requirement of an EMT as it occurs in vivo [56,57].…”

Section: An Alternative Developmental Mode?mentioning

confidence: 99%

Dynamics of anteroposterior axis establishment in a mammalian embryo-like system

Anlaş

Gritti

Oriola

et al. 2021

Preprint

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In the mammalian embryo, specification of the anteroposterior (AP) axis demarcates one of the first steps of body plan formation. While this process requires interactions with extra-embryonic tissues in the native embryo, minimal in vitro systems from embryonic stem cells (ESCs) undergo initial AP polarization in the absence of any localized, external cues. This self-organizing potential of stem cells remains not well understood. Here, we study such an initial symmetry breaking event in gastruloids, an established in vitro model for mammalian body plan formation, using the mesodermal marker gene Brachyury or T (Bra/T) to denote the onset of AP axis specification and concomitant germ layer formation. Through aggregate fusion experiments and manipulation of initial culture conditions as well as key developmental signalling pathways, we probe the dynamics of Bra/T polarization. We further conduct single-cell (sc) RNA sequencing of gastruloids at early stages to identify incipient molecular signatures of germ layer commitment and differences between Bra/T+ and Bra/T- populations during as well as after symmetry breaking. Moreover, we transcriptionally compare early development of gastruloids to the mouse embryo and conclude that gastruloids reproducibly undergo AP axis and germ layer specification in a parallel, but distinct manner: While their primed pluripotent cell populations adopt a more mesenchymal state in lieu of an epithelial epiblast-like transcriptome, the emerging mesendodermal lineages in vitro are nevertheless similar to their in vivo equivalents. Altogether, this study provides a comprehensive analysis of self-organized body plan establishment in a minimal in vitro system of early mammalian patterning and highlights the regulative capacity of mESCs, thereby shedding light on underlying principles of axial polarity formation.

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Section: An Alternative Developmental Mode?mentioning

confidence: 99%

Dynamics of anteroposterior axis establishment in a mammalian embryo-like system

Anlaş

Gritti

Oriola

et al. 2021

Preprint

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“…We have previously shown that gastruloids develop an endodermal primitive gut tube-like structure (Vianello and Lutolf, 2020), which forms close to the cardiac compartment (Rossi et al, 2020). It is known that endoderm-derived factors are needed to guide hemogenic fate and HSC development (Baron, 2003; Belaoussoff et al, 1998; Miura and Wilt, 1969; Pardanaud and Dieterlen-Lièvre, 1999; Peeters et al, 2009; Wilt, 1965).…”

Section: Discussionmentioning

confidence: 99%

Gastruloids asin vitromodels of embryonic blood development with spatial and temporal resolution

Rossi

Giger

Huebscher

et al. 2021

Preprint

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Gastruloids are three-dimensional embryonic organoids that reproduce key features of early mammalian development in vitro with unique scalability, accessibility, and spatiotemporal similarity to real embryos. Recently, we adapted gastruloid culture conditions to promote cardiovascular development. In this work, we extended these conditions to capture features of embryonic blood development through a combination of immunophenotyping, detailed transcriptomics analysis, and identification of blood stem/progenitor cell potency. We uncovered the emergence of blood progenitor and erythroid-like cell populations in late gastruloids and showed the multipotent clonogenic capacity of these cells, both in vitro and after transplantation into irradiated mice. We also identified the spatial localization near a vessel-like plexus in the anterior of gastruloids with similarities to the emergence of blood stem cells in the embryo. These results highlight the potential and applicability of gastruloids to the in vitro study of complex processes in embryonic blood development with spatiotemporal fidelity.

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“…In the years following their discovery, more advanced mouse 3D gastruloid models were developed that are able to generate brain [18,19], somite [20,21], neural tube [21], gut tube [21,22], and beating heart [23] -like structures (Figure 1A) [30]. In addition, recent advances resulted in human ES cell-based elongating mesodermal EBs [38], in human ES cell-based 3D gastruloids (Figure 1B) [24], in human ES and human induced pluripotent stem (iPS) cellbased neural tube-like structures [39], and in human iPS cell-based structures ['elongating multi-lineage organized (EMLO) gastruloids'] that develop embryonic central and peripheral neurons that interact with co-developing trunk mesendodermal tissues [40].…”

Section: D Gastruloids: Origin and Basic Conceptsmentioning

confidence: 99%

“…The discovery that pluripotent stem cells can be coaxed into embryo-like structures (Box 3) resulted in the development of model systems, such as: (i) ETS/X embryos [4][5][6]; post-implantation amniotic sac embryoid (PASE) models [7,8]; human epiblast models [9]; micropatterns (which were recently relabeled as '2D gastruloids') [10][11][12][13][14][15]; and gastruloids (which were recently relabeled as '3D gastruloids' to avoid confusion with 2D gastruloids) [16][17][18][19][20][21][22][23][24][25], that allow in vitro studies into the processes that occur during mammalian gastrulation. Similar to other stem Gastruloids provide fundamental new insights into embryonic development and may have applications for highthroughput studies into normal and pathological development in the near future.…”

mentioning

confidence: 99%

“…In this review, we specifically zoom in on mammalian (mouse and human) 3D gastruloids, which we here define as: 'Three dimensional aggregates of pluripotent stem cells that, under appropriate culture conditions, develop an embryo-like organization with three orthogonal axes and a precise distribution of the multiple derivatives of the three germ layers'. The 3D gastruloids generate most embryonic tissues with spatial and temporal precision in vitro [16,20,21,23,25,30,32], however, in contrast to mammalian embryos, they do not start from a single-layered epithelial state, they do not undergo any classical EMT-related mechanisms [22,33,34], and they do not form a primitive streak. These observations suggest that mammalian cells might be able to undergo a gastrulation-like process in an EMT-and primitive streak-independent manner and illustrate how observations made with gastruloids can challenge classical textbook paradigms of gastrulation.…”

mentioning

confidence: 99%

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3D gastruloids: a novel frontier in stem cell-based in vitro modeling of mammalian gastrulation

Brink

Oudenaarden

2021

Trends in Cell Biology

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3D gastruloids, aggregates of embryonic stem cells that recapitulate key aspects of gastrula-stage embryos, have emerged as a powerful tool to study the early stages of mammalian post-implantation development in vitro. Owing to their tractable nature and the relative ease by which they can be generated in large numbers, 3D gastruloids provide an unparalleled opportunity to study normal and pathological embryogenesis from a bottom-up perspective and in a highthroughput manner. Here, we review how gastruloid models can be exploited to deepen our understanding of mammalian development. In addition, we discuss current limitations, potential clinical applications, and ethical implications of this emerging model system. Stem cell-based embryo models: new tools to study mammalian gastrulation in vitro HighlightsGastruloids, 3D aggregates of embryonic stem cells that recapitulate the axial organization of post-implantation embryos, have emerged as a powerful tool to study embryonic development in vitro.Recent improvements have resulted in more complex mouse 3D gastruloid models that generate brain, somite, neural tube, gut tube, and beating heart-like structures in vitro and led to the first human versions of the 3D gastruloid system.

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In vitroendoderm emergence and self-organisation in the absence of extraembryonic tissues and embryonic architecture

Cited by 36 publications

References 90 publications

Dynamics of anteroposterior axis establishment in a mammalian embryo-like system

Dynamics of anteroposterior axis establishment in a mammalian embryo-like system

Gastruloids asin vitromodels of embryonic blood development with spatial and temporal resolution

3D gastruloids: a novel frontier in stem cell-based in vitro modeling of mammalian gastrulation

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