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<p>Pluripotency, the ability to generate all body cell types, emerges in a disorganized embryonic cell mass. After implantation, these cells form a columnar epithelium and initiate lumenogenesis. During gastrulation, some undergo epithelial-to-mesenchymal transition to form the primitive streak (PS). The signals controlling these events in humans are largely unknown. Here, to study them, we developed a chemically defined 3D model where conventional pluripotent stem cells self-organize into a columnar epithelium with a lumen, from which PS-like cells emerge. We show that early TGFβ family inhibition prevents epithelial identity, also in murine 3D embryo models and in embryos. ZNF398 acts downstream of TGFβ1, activating the epithelial master regulator ESRP1 while repressing mesenchymal factors CDH2 and ZEB2. After epithelium formation, TGFβ1 stimulation is dispensable for its maintenance. However, treatment via ACTIVIN—a distinct TGFβ family ligand—induces PS efficiently. Thus, signalling of the TGFβ family dynamically governs pluripotent epiblast epithelial identity.</p>

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A human epiblast model reveals dynamic TGFβ-mediated control of epithelial identity during mammalian epiblast development

  • 期刊论文

  • 发表日期：

    2025年12月3日

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  • Irene Zorzan,
  • Elena Carbognin,
  • Andrea Lauria,
  • Valentina Proserpio,
  • Davide Benvegnù,
  • Federica Bertelli,
  • Susana De Juambelz Urías,
  • Caterina Dalrio,
  • Giorgia Panebianco,
  • Rebecca Scarfò,
  • Eleonora Pensabene,
  • Mattia Arboit,
  • Irene Paolucci,
  • Andrea Drusin,
  • Dario Bizzotto,
  • Monika Sledziowska,
  • Paola Braghetta,
  • Andrea Ditadi,
  • Gianluca Amadei,
  • Salvatore Oliviero,
  • Graziano Martello

摘要

Pluripotency, the ability to generate all body cell types, emerges in a disorganized embryonic cell mass. After implantation, these cells form a columnar epithelium and initiate lumenogenesis. During gastrulation, some undergo epithelial-to-mesenchymal transition to form the primitive streak (PS). The signals controlling these events in humans are largely unknown. Here, to study them, we developed a chemically defined 3D model where conventional pluripotent stem cells self-organize into a columnar epithelium with a lumen, from which PS-like cells emerge. We show that early TGFβ family inhibition prevents epithelial identity, also in murine 3D embryo models and in embryos. ZNF398 acts downstream of TGFβ1, activating the epithelial master regulator ESRP1 while repressing mesenchymal factors CDH2 and ZEB2. After epithelium formation, TGFβ1 stimulation is dispensable for its maintenance. However, treatment via ACTIVIN—a distinct TGFβ family ligand—induces PS efficiently. Thus, signalling of the TGFβ family dynamically governs pluripotent epiblast epithelial identity.