Mesenchymal-epithelial transition regulates initiation of pluripotency exit before gastrulation

ABSTRACT The pluripotent epiblast gives rise to all tissues and organs in the adult body. Its differentiation starts at gastrulation, when the epiblast generates mesoderm and endoderm germ layers through epithelial-mesenchymal transition (EMT). Although gastrulation EMT coincides with loss of epiblast pluripotency, pluripotent cells in development and in vitro can adopt either mesenchymal or epithelial morphology. The relationship between epiblast cellular morphology and its pluripotency is not well understood. Here, using chicken epiblast and mammalian pluripotency stem cell (PSC) models, we show that PSCs undergo a mesenchymal-epithelial transition (MET) prior to EMT-associated pluripotency loss. Epiblast MET and its subsequent EMT are two distinct processes. The former, a partial MET, is associated with reversible initiation of pluripotency exit, whereas the latter, a full EMT, is associated with complete and irreversible pluripotency loss. We provide evidence that integrin-mediated cell-matrix interaction is a key player in pluripotency exit regulation. We propose that epiblast partial MET is an evolutionarily conserved process among all amniotic vertebrates and that epiblast pluripotency is restricted to an intermediate cellular state residing between the fully mesenchymal and fully epithelial states. Highlighted Article: Amniote epiblast reaches full epithelialization status before gastrulation. A partial mesenchymal-to-epithelial transition process regulates its pluripotency exit.

• Publication year

  2019

• Venue

  Development

• Publication date

  2019-05-30

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1242/dev.184960PMID 32014865
• 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.

• Non-redundant functions of EMT transcription factors

  2019influential reference
• Biomechanical regulation of EMT and epithelial morphogenesis in amniote epiblast

  2019cited by this paper
• Human Pluripotency Is Initiated and Preserved by a Unique Subset of Founder Cells.

  2019cited by this paper
• The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell

  2018cited by this paper
• Epiblast formation by Tead-Yap-dependent expression of pluripotency factors and competitive elimination of unspecified cells

  2018cited by this paper
• Pluripotency Deconstructed

  2018cited by this paper
• Micropattern differentiation of mouse pluripotent stem cells recapitulates embryo regionalized cell fate patterning

  2018cited by this paper
• Mouse ICM Organoids Reveal Three-Dimensional Cell Fate Clustering

  2018cited by this paper
• GRHL2-Dependent Enhancer Switching Maintains a Pluripotent Stem Cell Transcriptional Subnetwork after Exit from Naive Pluripotency.

  2018cited by this paper
• Snail collaborates with EGR-1 and SP-1 to directly activate transcription of MMP 9 and ZEB1

  2017influential reference
• Cytoplasmic and Nuclear TAZ Exert Distinct Functions in Regulating Primed Pluripotency

  2017cited by this paper
• The GRHL2/ZEB Feedback Loop—A Key Axis in the Regulation of EMT in Breast Cancer

  2017cited by this paper
• Systematic analysis of transcription start sites in avian development

  2017cited by this paper
• Integrin and dystroglycan compensate each other to mediate laminin-dependent basement membrane assembly and epiblast polarization.

  2017cited by this paper
• Stem Cell Differentiation as a Non-Markov Stochastic Process

  2017cited by this paper
• Pluripotent state transitions coordinate morphogenesis in mouse and human embryos

  2017cited by this paper
• Three mechanisms control E-cadherin localization to the zonula adherens

  2016cited by this paper
• The evolutionally-conserved function of group B1 Sox family members confers the unique role of Sox2 in mouse ES cells

  2016cited by this paper
• EMT: 2016.

  2016cited by this paper
• Self-organization of human embryonic stem cells on micropatterns

  2016cited by this paper
• Inappropriate cadherin switching in the mouse epiblast compromises proper signaling between the epiblast and the extraembryonic ectoderm during gastrulation

  2016cited by this paper
• The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

  2016cited by this paper
• Self-organization of the in vitro attached human embryo

  2016cited by this paper
• A developmental coordinate of pluripotency among mice, monkeys and humans

  2016cited by this paper
• Inhibition of Focal Adhesion Kinase Signaling by Integrin α6β1 Supports Human Pluripotent Stem Cell Self‐Renewal

  2016cited by this paper
• Inhibition of the integrin signal constitutes a mouse iPS cell niche

  2016cited by this paper
• GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification

  2016cited by this paper
• Integrin-Associated Focal Adhesion Kinase Protects Human Embryonic Stem Cells from Apoptosis, Detachment, and Differentiation

  2016cited by this paper
• Super-Resolution Mapping of Neuronal Circuitry With an Index-Optimized Clearing Agent.

  2016cited by this paper
• YAP Induces Human Naive Pluripotency

  2016cited by this paper
• Dynamic stem cell states: naive to primed pluripotency in rodents and humans

  2016cited by this paper
• Author response: Characterization of the finch embryo supports evolutionary conservation of the naive stage of development in amniotes

  2015cited by this paper
• Epiblast morphogenesis before gastrulation.

  2015cited by this paper
• Defining the three cell lineages of the human blastocyst by single-cell RNA-seq

  2015cited by this paper
• TAZ regulates cell proliferation and epithelial–mesenchymal transition of human hepatocellular carcinoma

  2015influential reference
• Characterization of the finch embryo supports evolutionary conservation of the naive stage of development in amniotes

  2015cited by this paper
• Verification of chicken Nanog as an epiblast marker and identification of chicken PouV as Pou5f3 by newly raised antibodies

  2015cited by this paper
• Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells

  2015cited by this paper
• Self-Organizing Properties of Mouse Pluripotent Cells Initiate Morphogenesis upon Implantation

  2014cited by this paper
• A method to recapitulate early embryonic spatial patterning in human embryonic stem cells

  2014cited by this paper
• Molecular mechanisms of epithelial–mesenchymal transition

  2014cited by this paper
• Hypoxia induces re‐entry of committed cells into pluripotency

  2013cited by this paper
• Origins and implications of pluripotent stem cell variability and heterogeneity

  2013cited by this paper
• Epiblast integrity requires CLASP and Dystroglycan-mediated microtubule anchoring to the basal cortex

  2013cited by this paper
• Biomimetic aggrecan reduces cartilage extracellular matrix from degradation and lowers catabolic activity in ex vivo and in vivo models.

  2013cited by this paper
• Mammalian genes induce partially reprogrammed pluripotent stem cells in non-mammalian vertebrate and invertebrate species

  2013cited by this paper
• Suppression of the epithelial-mesenchymal transition by Grainyhead-like-2.

  2012cited by this paper
• The hypoblast (visceral endoderm): an evo-devo perspective

  2012cited by this paper
• Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells.

  2011cited by this paper
• Modeling familial Alzheimer's disease with induced pluripotent stem cells.

  2011cited by this paper
• Study of Pluripotency Markers in Zebrafish Embryos and Transient Embryonic Stem Cell Cultures

  2011cited by this paper
• Nocodazole Treatment Decreases Expression of Pluripotency Markers Nanog and Oct4 in Human Embryonic Stem Cells

  2011cited by this paper
• Activin/TGF-beta signaling regulates Nanog expression in the epiblast during gastrulation.

  2011cited by this paper
• Isolation of epiblast stem cells from preimplantation mouse embryos.

  2011cited by this paper
• Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions

  2010cited by this paper
• Long-term self-renewal of human pluripotent stem cells on human recombinant laminin-511

  2010cited by this paper
• Transcriptomic landscape of the primitive streak

  2010cited by this paper
• Distinguishing Between Mouse and Human Pluripotent Stem Cell Regulation: The Best Laid Plans of Mice and Men

  2010cited by this paper
• Involvement of Dystroglycan in Epithelial-Mesenchymal Transition during Chick Gastrulation

  2010cited by this paper
• Integrins stimulate E-cadherin-mediated intercellular adhesion by regulating Src-kinase activation and actomyosin contractility

  2010cited by this paper
• Polymeric nanoparticle-based activatable near-infrared nanosensor for protease determination in vivo.

  2009cited by this paper
• Naive and primed pluripotent states.

  2009cited by this paper
• Intracellular polarity protein PAR‐1 regulates extracellular laminin assembly by regulating the dystroglycan complex

  2009influential reference
• Epithelial to mesenchymal transition during gastrulation: An embryological view

  2008cited by this paper
• TAZ Promotes Cell Proliferation and Epithelial-Mesenchymal Transition and Is Inhibited by the Hippo Pathway

  2008cited by this paper
• Recombinant Vitronectin Is a Functionally Defined Substrate That Supports Human Embryonic Stem Cell Self‐Renewal via αVβ5 Integrin

  2008cited by this paper
• RhoA and microtubule dynamics control cell–basement membrane interaction in EMT during gastrulation

  2008cited by this paper
• The amniote primitive streak is defined by epithelial cell intercalation before gastrulation

  2007cited by this paper
• New cell lines from mouse epiblast share defining features with human embryonic stem cells

  2007cited by this paper
• Nanog safeguards pluripotency and mediates germline development

  2007cited by this paper
• A ROCK inhibitor permits survival of dissociated human embryonic stem cells

  2007cited by this paper
• Induction of pluripotent stem cells from adult human fibroblasts by defined factors.

  2007cited by this paper
• The Oct4 homologue PouV and Nanog regulate pluripotency in chicken embryonic stem cells

  2007cited by this paper
• Cell movement during chick primitive streak formation.

  2006cited by this paper
• Negative regulation of primitive hematopoiesis by the FGF signaling pathway.

  2006cited by this paper
• The primitive streak

  2004cited by this paper
• Integrin-linked kinase (ILK) is required for polarizing the epiblast, cell adhesion, and controlling actin accumulation.

  2003cited by this paper
• Conformational regulation of integrin structure and function.

  2002cited by this paper
• Features of polyingression and primitive streak ingression through the basal lamina in the chicken blastoderm

  1991cited by this paper
• Localization of the tight junction protein, ZO-1, is modulated by extracellular calcium and cell-cell contact in Madin-Darby canine kidney epithelial cells

  1988cited by this paper
• Human blastogenesis. Formation of the extraembryonic cavities.

  1987cited by this paper
• Primary hypoblast development in the chick

  1982cited by this paper
• From cleavage to primitive streak formation: a complementary normal table and a new look at the first stages of the development of the chick. II. Microscopic anatomy and cell population dynamics.

  1980cited by this paper
• Origin and differentiation of the yolk sac and extraembryonic mesoderm in presomite human and rhesus monkey embryos.

  1978cited by this paper
• From cleavage to primitive streak formation: a complementary normal table and a new look at the first stages of the development of the chick. I. General morphology.

  1976cited by this paper
• The development of primordial and definitive amniotic cavities in early Rhesus monkey and human embryos.

  1975cited by this paper
• Organization and fine structure of epithelium and mesenchyme in the developing chick embryo

  1968cited by this paper
• The epigenetics of birds

  1952cited by this paper

• NR6A1 is essential for neural crest cell specification, formation and survival

  2026cites this paper
• Derivation of embryonic stem cells across avian species.

  2025cites this paper
• Biological boundary conditions regulate the internalization of Aspergillus fumigatus conidia by alveolar cells

  2024cites this paper
• Epithelial–mesenchymal transition in tissue repair and degeneration

  2024cites this paper
• ETV2 induces endothelial, but not hematopoietic, lineage specification in birds

  2024cites this paper
• Biomarkers and experimental models for cancer immunology investigation

  2023cites this paper
• Inhibition of Epithelial-Mesenchymal Transition Maintains Stemness in Human Amniotic Epithelial Cells

  2022cites this paper
• Mesenchymal-to-epithelial transition of osteoblasts induced by Fam20c knockout

  2022cites this paper
• Dual role of Ovol2 on the germ cell lineage segregation during gastrulation in mouse embryogenesis.

  2022cites this paper
• Efficient reprogramming of human fibroblasts using RNA reprogramming with DAPT and iDOT1L under normoxia conditions

  2022cites this paper
• Naïve pluripotent-like characteristics of non-tumorigenic Muse cells isolated from human amniotic membrane

  2022cites this paper
• Mesothelial fusion mediates chorioallantoic membrane formation

  2022cites this paper
• In vitro models of pre- and post-gastrulation embryonic development.

  2022cites this paper
• Cell-cell contact-driven EphB1 cis- and trans- signalings regulate cancer stem cells enrichment after chemotherapy

  2022cites this paper
• Involvement of LIMK2 in actin cytoskeleton remodeling during the definitive endoderm differentiation

  2021cites this paper
• Epithelial-Mesenchymal Transition Drives Three-Dimensional Morphogenesis in Mammalian Early Development

  2021influential citation
• The primitive streak and cellular principles of building an amniote body through gastrulation

  2021cites this paper
• What we can learn from embryos to understand the mesenchymal-to-epithelial transition in tumor progression.

  2021cites this paper
• Defining epithelial-mesenchymal transitions in animal development.

  2021cites this paper
• C-STEM: ENGINEERING NICHE-LIKE MICRO-COMPARTMENTS FOR OPTIMAL AND SCALE-INDEPENDENT EXPANSION OF HUMAN PLURIPOTENT STEM CELLS IN BIOREACTORS

  2021cites this paper
• Novel Methylation Biomarkers for Colorectal Cancer Prognosis

  2021cites this paper
• A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

  2020cites this paper
• In vitro endoderm emergence and self-organisation in the absence of extraembryonic tissues and embryonic architecture

  2020cites this paper
• Mechanisms of human embryo development: from cell fate to tissue shape and back

  2020cites this paper