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Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing

Author

Listed:
  • Thomas Legier

    (NeuroMarseille)

  • Diane Rattier

    (NeuroMarseille)

  • Jack Llewellyn

    (NeuroMarseille)

  • Thomas Vannier

    (NeuroMarseille)

  • Benoit Sorre

    (Laboratoire Physico Chimie Curie)

  • Flavio Maina

    (NeuroMarseille)

  • Rosanna Dono

    (NeuroMarseille)

Abstract

The processes of primitive streak formation and fate specification in the mammalian epiblast rely on complex interactions between morphogens and tissue organization. Little is known about how these instructive cues functionally interact to regulate gastrulation. We interrogated the interplay between tissue organization and morphogens by using human induced pluripotent stem cells (hiPSCs) downregulated for the morphogen regulator GLYPICAN-4, in which defects in tight junctions result in areas of disrupted epithelial integrity. Remarkably, this phenotype does not affect hiPSC stemness, but impacts on cell fate acquisition. Strikingly, cells within disrupted areas become competent to perceive the gastrulation signals BMP4 and ACTIVIN A, an in vitro surrogate for NODAL, and thus differentiate into mesendoderm. Yet, disruption of epithelial integrity sustains activation of BMP4 and ACTIVIN A downstream effectors and correlates with enhanced hiPSC endoderm/mesoderm differentiation. Altogether, our results disclose epithelial integrity as a key determinant of TGF-β activity and highlight an additional mechanism guiding morphogen sensing and spatial cell fate change within an epithelium.

Suggested Citation

  • Thomas Legier & Diane Rattier & Jack Llewellyn & Thomas Vannier & Benoit Sorre & Flavio Maina & Rosanna Dono, 2023. "Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35965-8
    DOI: 10.1038/s41467-023-35965-8
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    References listed on IDEAS

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    1. Zhechun Zhang & Steven Zwick & Ethan Loew & Joshua S. Grimley & Sharad Ramanathan, 2019. "Mouse embryo geometry drives formation of robust signaling gradients through receptor localization," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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    3. Innokenty Woichansky & Carlo Antonio Beretta & Nicola Berns & Veit Riechmann, 2016. "Three mechanisms control E-cadherin localization to the zonula adherens," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
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