Glycolytic activity instructs germ layer proportions through regulation of Nodal and Wnt signaling
Metabolic pathways can influence cell fate decisions, yet their regulative role during embryonic development remains poorly understood. Here, we demonstrate an instructive role of glycolytic activity in regulating signaling pathways involved in mesoderm and endoderm specification. Using a mouse embryonic stem cell (mESC)-based in vitro model for gastrulation, we found that glycolysis inhibition increases ectodermal cell fates at the expense of mesodermal and endodermal lineages. We demonstrate that this relationship is dose dependent, enabling metabolic control of germ layer proportions through exogenous glucose levels. We further show that glycolysis acts as an upstream regulator of Nodal and Wnt signaling and that its influence on cell fate specification can be decoupled from its effects on growth. Finally, we confirm the generality of our findings using a human gastrulation model. Our work underscores the dependence of signaling pathways on metabolic conditions and provides mechanistic insight into the nutritional regulation of cell fate decision-making.
Authors
- Miki Ebisuya (ORCID: https://orcid.org/0000-0003-1854-7496)
- Elisa Hahn (ORCID: https://orcid.org/0000-0002-4064-1828)
- Kiran Raosaheb Patil (ORCID: https://orcid.org/0000-0002-6166-8640)
- Vikas Trivedi (ORCID: https://orcid.org/0000-0003-0953-0553)
- Kristina S. Stapornwongkul (ORCID: https://orcid.org/0000-0002-7299-9672)
- Kate Williamson
- Patryk Poliński (ORCID: https://orcid.org/0000-0002-1733-7983)
- Idse Heemskerk (ORCID: https://orcid.org/0000-0002-8861-7712)
- Laura Palau (ORCID: https://orcid.org/0000-0003-4346-6989)
- Krisztina Arató (ORCID: https://orcid.org/0000-0003-0366-0998)
- Nicola Gritti (ORCID: https://orcid.org/0000-0002-7637-4258)
- Mireia Osuna Lopez (ORCID: https://orcid.org/0000-0001-7724-444X)
- Kerim Anlaş (ORCID: https://orcid.org/0000-0002-9272-8626)
- LiAng Yao (ORCID: https://orcid.org/0000-0002-7158-1629)
Institutions
- European Molecular Biology Organization (DE)
- University of Cambridge (GB)
- University of Michigan (US)
- European Molecular Biology Laboratory (ES)
- European Molecular Biology Laboratory (DE)
- Center for Systems Biology Dresden (DE)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Medical Research Council (GB)
Publication Details
- Journal
- Cell stem cell
- Published
- 2025-04-16
- DOI
- https://doi.org/10.1016/j.stem.2025.03.011
- Citations
- 18
- Primary Topic
- Plant Molecular Biology Research
- Type
- article
- Field-Weighted Citation Impact
- 31.50
Funders
- National Science Foundation
- Gordon and Betty Moore Foundation
- Human Frontier Science Program
- European Molecular Biology Laboratory
- Human Frontier Science Program
- National Institute of General Medical Sciences
- Kavli Institute for Theoretical Physics, University of California, Santa Barbara
- H2020 European Research Council
- H2020 Marie Skłodowska-Curie Actions
- HORIZON EUROPE European Research Council