Mechanical Tension Promotes Formation of Gastrulation-like Nodes and Patterns Mesoderm Specification in Human Embryonic Stem Cells.

Embryogenesis is directed by morphogens that induce differentiation within a defined tissue geometry. Tissue organization is mediated by cell-cell and cell-extracellular matrix (ECM) adhesions and is modulated by cell tension and tissue-level forces. Whether cell tension regulates development by modifying morphogen signaling is less clear. Human embryonic stem cells (hESCs) exhibit an intrinsic capacity for self-organization, which motivates their use as a tractable model of early human embryogenesis. We engineered patterned substrates that recapitulate the biophysical properties of the early embryo and mediate the self-organization of "gastrulation-like" nodes in cultured hESCs. Tissue geometries that generated local nodes of high cell-adhesion tension directed the spatial patterning of the BMP4-dependent "gastrulation-like" phenotype by enhancing phosphorylation and junctional release of β-catenin to promote Wnt signaling and mesoderm specification. Furthermore, direct force application via mechanical stretching promoted BMP-dependent mesoderm specification, confirming that tissue-level forces can directly regulate cell fate specification in early human development.

• Publication year

  2020

• Venue

  Developmental Cell

• Publication date

  2020-11-10

• Fields of study

  Biology, Medicine, Engineering

• Identifiers
  DOI 10.1016/j.devcel.2020.10.015PMID 33207224PMCID PMC7755684
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The cellular and molecular mechanisms that establish the mechanics of Drosophila gastrulation.

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• Basement membrane remodelling regulates mouse embryogenesis

  2020cited by this paper
• Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids

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• Cellular, molecular, and biophysical control of epithelial cell intercalation.

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• Molecular anatomy of the pre-primitive-streak chick embryo

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  2019cited by this paper
• A 3D model of a human epiblast reveals BMP4-driven symmetry breaking

  2019cited by this paper
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  2019cited by this paper
• Controlled modelling of human epiblast and amnion development using stem cells

  2019cited by this paper
• Patterning the Geometry of Human Embryonic Stem Cell Colonies on Compliant Substrates to Control Tissue-Level Mechanics.

  2019cited by this paper
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  2019cited by this paper
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  2019cited by this paper
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  2019cited by this paper
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  2019cited by this paper
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  2018cited by this paper
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  2018cited by this paper
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  2018cited by this paper
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  2018cited by this paper
• Prediction and control of symmetry breaking in embryoid bodies by environment and signal integration

  2018cited by this paper
• A wave of WNT signaling balanced by secreted inhibitors controls primitive streak formation in micropattern colonies of human embryonic stem cells

  2018cited by this paper
• Third-generation in situ hybridization chain reaction: multiplexed, quantitative, sensitive, versatile, robust

  2018influential reference
• CellProfiler 3.0: Next-generation image processing for biology

  2018influential reference
• The major β-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation in vivo

  2018influential reference
• Self-assembly of embryonic and two extra-embryonic stem cell types into gastrulating embryo-like structures

  2018cited by this paper
• Deconstructing and reconstructing the mouse and human early embryo

  2018cited by this paper
• A stepwise model of reaction-diffusion and positional information governs self-organized human peri-gastrulation-like patterning

  2017cited by this paper
• Antagonistic Activities of Sox2 and Brachyury Control the Fate Choice of Neuro-Mesodermal Progenitors.

  2017cited by this paper
• A pluripotent stem cell-based model for post-implantation human amniotic sac development

  2017cited by this paper
• Embryoids, organoids and gastruloids: new approaches to understanding embryogenesis

  2017cited by this paper
• Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro

  2017cited by this paper
• Regulation of gastrulation movements by emergent cell and tissue interactions.

  2017cited by this paper
• A Balance between Secreted Inhibitors and Edge Sensing Controls Gastruloid Self-Organization.

  2016influential reference
• Monitoring developmental force distributions in reconstituted embryonic epithelia.

  2016influential reference
• Interfacial geometry dictates cancer cell tumorigenicity.

  2016cited by this paper
• Tissue Mechanics Orchestrate Wnt-Dependent Human Embryonic Stem Cell Differentiation.

  2016influential reference
• Mechanics of neurulation: From classical to current perspectives on the physical mechanics that shape, fold, and form the neural tube

  2016cited by this paper
• Self-organisation of the human embryo in the absence of maternal tissues

  2016cited by this paper
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  2015cited by this paper
• Desktop aligner for fabrication of multilayer microfluidic devices.

  2015cited by this paper
• Role of physical forces in embryonic development.

  2015cited by this paper
• Mechanics of tissue compaction.

  2015cited by this paper
• The tissue mechanics of vertebrate body elongation and segmentation.

  2015cited by this paper
• A method to recapitulate early embryonic spatial patterning in human embryonic stem cells

  2014influential reference
• Morphomechanics: transforming tubes into organs.

  2014cited by this paper
• Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells

  2014cited by this paper
• Local cell interactions and self-amplifying individual cell ingression drive amniote gastrulation

  2014influential reference
• Evolutionary conservation of early mesoderm specification by mechanotransduction in Bilateria

  2013cited by this paper
• On the role of intrinsic and extrinsic forces in early cardiac S‐looping

  2013cited by this paper
• Multiplex Genome Engineering Using CRISPR/Cas Systems

  2013cited by this paper
• Exploring the link between human embryonic stem cell organization and fate using tension-calibrated extracellular matrix functionalized polyacrylamide gels.

  2012cited by this paper
• A series of normal stages in the development of the chick embryo. 1951.

  2012cited by this paper
• Spatial organization of the extracellular matrix regulates cell–cell junction positioning

  2012influential reference
• Fiji: an open-source platform for biological-image analysis

  2012influential reference
• A Positive Role of Cadherin in Wnt/β-Catenin Signalling during Epithelial-Mesenchymal Transition

  2011cited by this paper
• Geometric cues for directing the differentiation of mesenchymal stem cells

  2010cited by this paper
• Tissue geometry patterns epithelial–mesenchymal transition via intercellular mechanotransduction

  2010cited by this paper
• Wnt signaling and the polarity of the primary body axis.

  2009cited by this paper
• Towards an integrated view of Wnt signaling in development

  2009cited by this paper
• Mechanism of eukaryotic homologous recombination.

  2008cited by this paper
• Live imaging of cell protrusive activity, and extracellular matrix assembly and remodeling during morphogenesis in the frog, Xenopus laevis

  2008cited by this paper
• Wnt/beta-catenin signaling in development and disease.

  2006cited by this paper
• Chromatin-Binding Regions of EBNA1 Protein Facilitate the Enhanced Transfection of Epstein–Barr Virus-Based Vectors

  2006cited by this paper
• Canonical Wnt signaling is required for development of embryonic stem cell-derived mesoderm

  2006cited by this paper
• Tissue Geometry Determines Sites of Mammary Branching Morphogenesis in Organotypic Cultures

  2006cited by this paper
• beta-Catenin: a pivot between cell adhesion and Wnt signalling.

  2005cited by this paper
• The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin.

  2005cited by this paper
• Cell migration during gastrulation.

  2005cited by this paper
• Expression of all Wnt genes and their secreted antagonists during mouse blastocyst and postimplantation development

  2005cited by this paper
• Distinct molecular forms of β-catenin are targeted to adhesive or transcriptional complexes

  2004cited by this paper
• Induction and patterning of the primitive streak, an organizing center of gastrulation in the amniote

  2004cited by this paper
• The expression of gelatinase A (MMP-2) is required for normal development of zebrafish embryos

  2003cited by this paper
• The hypoblast of the chick embryo positions the primitive streak by antagonizing nodal signaling.

  2002cited by this paper
• Improved method for chick whole‐embryo culture using a filter paper carrier

  2001cited by this paper
• Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity.

  2000cited by this paper
• Early development of Xenopus laevis : a laboratory manual

  2000cited by this paper
• Effective amplification of long targets from cloned inserts and human genomic DNA.

  1994cited by this paper
• Integrative mechanisms in development of the early chick blastoderm. I. Regulative potentiality of separated parts

  1960cited by this paper
• A series of normal stages in the development of the chick embryo

  1951cited by this paper

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• Progress in stem cell-based embryo models and their applications in developmental biology and biomedicine

  2026cites this paper
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• Gastruloids reveal alternative morphogenetic routes for body axis elongation with distinct cytoskeletal dependencies

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• Enhancer remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm.

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  2025cites this paper
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