Specialized signaling centers direct cell fate and spatial organization in a mesodermal organoid model
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.
Authors
- Martin Weigert (ORCID: https://orcid.org/0000-0002-7780-9057)
- Matthias P. Lütolf (ORCID: https://orcid.org/0000-0002-5898-305X)
- Gioele La Manno (ORCID: https://orcid.org/0000-0003-1428-8757)
- Marion Leleu (ORCID: https://orcid.org/0000-0002-1800-0821)
- Alejandro Castilla‐Ibeas (ORCID: https://orcid.org/0000-0001-9095-1149)
- K. H. Hu (ORCID: https://orcid.org/0009-0009-1870-3373)
- Georgios Tsissios (ORCID: https://orcid.org/0000-0002-5219-616X)
- Hwanseok Jang (ORCID: https://orcid.org/0000-0002-1700-5962)
- Evangelia Skoufa (ORCID: https://orcid.org/0009-0000-3198-3968)
- Jixing Zhong (ORCID: https://orcid.org/0000-0002-1511-8664)
- Albert Dominguez Mantes (ORCID: https://orcid.org/0000-0002-6224-0750)
- Can Aztekin (ORCID: https://orcid.org/0000-0002-6544-9752)
- Antonio Herrera (ORCID: https://orcid.org/0000-0002-6248-1001)
- Oliver Kahre (ORCID: https://orcid.org/0009-0007-0813-3878)
- María A. Ros (ORCID: https://orcid.org/0000-0002-1224-7671)
- Louise Carrau (ORCID: https://orcid.org/0009-0000-6050-4372)
Institutions
- Roche (Switzerland) (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- Max Planck Society (DE)
- Instituto de Biomedicina y Biotecnología de Cantabria (ES)
- École Polytechnique Fédérale de Lausanne (CH)
- Technische Universität Dresden (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1126/sciadv.ady7682
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00