Specialized cytonemes induce self-organization of stem cells

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Spatial cellular organization is fundamental for embryogenesis. Remarkably, coculturing embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) recapitulates this process, forming embryolike structures. However, mechanisms driving ESC-TSC interaction remain elusive. We describe specialized ESC-generated cytonemes that react to TSC-secreted Wnts. Cytoneme formation and length are controlled by actin, intracellular calcium stores, and components of the Wnt pathway. ESC cytonemes select self-renewal- promoting Wnts via crosstalk between Wnt receptors, activation of ionotropic glutamate receptors (iGluRs), and localized calcium transients. This crosstalk orchestrates Wnt signaling, ESC polarization, ESC-TSC pairing, and consequently synthetic embryogenesis. Our results uncover ESC-TSC contact-mediated signaling, reminiscent of the glutamatergic neuronal synapse, inducing spatial selforganization and embryonic cell specification.

Original languageEnglish
Pages (from-to)7236-7244
Number of pages9
JournalProceedings of National Academy of Sciences USA
Issue number13
Early online date17 Mar 2020
Publication statusPublished - 31 Mar 2020


  • Cell signaling
  • Cell-cell communication
  • Development
  • Stem cell
  • Tissue formation


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