2. Academic Validation
  3. Specialized signaling centers direct cell fate and spatial organization in a mesodermal organoid model

Specialized signaling centers direct cell fate and spatial organization in a mesodermal organoid model

  • Sci Adv. 2025 Nov 28;11(48):eady7682. doi: 10.1126/sciadv.ady7682.
Evangelia Skoufa 1,  Jixing Zhong 1,  Kelly Hu 1 2,  Oliver Kahre 1,  Georgios Tsissios 1,  Louise Carrau 1,  Antonio Herrera 1,  Albert Dominguez Mantes 1,  Marion Leleu 3,  Alejandro Castilla-Ibeas 4,  Hwanseok Jang 1,  Martin Weigert 1 5,  Gioele La Manno 1,  Matthias Lutolf 1 6,  Marian Ros 4,  Can Aztekin 1 2
Affiliations

Affiliations

  • 1 School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne 1015, Switzerland.
  • 2 Friedrich Miescher Laboratory of the Max Planck Society, Tübingen 72076, Germany.
  • 3 Bioinformatics Competence Center, EPFL, Lausanne 1015, Switzerland.
  • 4 Department of Cellular and Molecular Signalling, Instituto de Biotecnología y Biomedicina de Cantabria (IBBTEC), CSIC-SODERCAN-University of Cantabria, Santander, Spain.
  • 5 Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), Technical University Dresden, Dresden, Germany.
  • 6 Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel 4058, Switzerland.
PMID: 41313763 DOI: 10.1126/sciadv.ady7682
Abstract

Specialized signaling centers orchestrate robust development and regeneration. Limb morphogenesis, for instance, requires interactions between the mesoderm and the signaling center apical-ectodermal ridge (AER), whose properties and role in cell fate decisions have remained challenging to dissect. To tackle this, we developed mouse embryonic stem cell (mESC)-based heterogeneous cultures and a three-dimensional (3D) Organoid model, termed budoids, comprising cells with AER, surface ectoderm, and mesoderm properties. mESCs were first induced into heterogeneous cultures that self-organized into domes in 2D. Aggregating these cultures formed mesodermal organoids with certain limb bud-like features in 3D, exhibiting chondrogenesis-based symmetry breaking and elongation. Using our organoids and quantitative in situ expression profiling, we uncovered that AER-like cells support nearby limb mesoderm and fibroblast identities while enhancing tissue polarization that permits distant cartilage formation. Together, our findings provide a powerful model to study epithelial signaling center-mesoderm interactions during morphogenesis and reveal the ability of signaling center AER cells to concurrently modulate cell fate and spatial organization.

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