Interplay between metabolic identities in the intestinal crypt supports stem cell function
Open accessAbstract
The small intestinal epithelium self-renews every four or five days. Intestinal stem cells (Lgr5+ crypt base columnar cells (CBCs)) sustain this renewal and reside between terminally differentiated Paneth cells at the bottom of the intestinal crypt. Whereas the signalling requirements for maintaining stem cell function and crypt homeostasis have been well studied, little is known about how metabolism contributes to epithelial homeostasis. Here we show that freshly isolated Lgr5+ CBCs and Paneth cells from the mouse small intestine display different metabolic programs. Compared to Paneth cells, Lgr5+ CBCs display high mitochondrial activity. Inhibition of mitochondrial activity in Lgr5+ CBCs or inhibition of glycolysis in Paneth cells strongly affects stem cell function, as indicated by impaired organoid formation. In addition, Paneth cells support stem cell function by providing lactate to sustain the enhanced mitochondrial oxidative phosphorylation in the Lgr5+ CBCs. Mechanistically, we show that oxidative phosphorylation stimulates p38 MAPK activation by mitochondrial reactive oxygen species signalling, thereby establishing the mature crypt phenotype. Together, our results reveal a critical role for the metabolic identity of Lgr5+ CBCs and Paneth cells in supporting optimal stem cell function, and we identify mitochondria and reactive oxygen species signalling as a driving force of cellular differentiation.
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In multiple tissue contexts, adult stem cells primarily engage in aerobic glycolysis.
“In multiple tissue contexts, adult stem cells have been found to primarily engage in aerobic glycolysis.”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [203]
Upon lineage commitment and differentiation, cells increase their oxidation of pyruvate in the TCA cycle and display enhanced OXPHOS.
“Upon lineage commitment and differentiation, however, cells increase their oxidation of pyruvate in the TCA cycle and display enhanced OXPHOS (203, 204, 205).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [203]
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- Authors
- Rodríguez-Colman, M. J., Schewe, M., Meerlo, M., Stigter, E., Gerrits, J., Pras-Raves, M., Sacchetti, A., Hornsveld, M., Oost, K. C., Snippert, H. J., Verhoeven-Duif, N., Fodde, R., & Burgering, B. M. T.
- Affiliations
- Erasmus MC (NL)
- University Medical Center Utrecht (NL)
- Utrecht University (NL)
- Corresponding author
- Burgering, Boudewijn M. T.
- ORCID
- Venue
- Nature
- Published
- 2017-03-08
- Volume
- 543
- Issue
- 7645
- Pages
- 424-427
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2594543006
- Cited by
- 522
- References
- 36
- Citations by year
- 2026: 46 · 2025: 58 · 2024: 56 · 2023: 59 · 2022: 58 · 2021: 67 · 2020: 66 · 2019: 41 · 2018: 50 · 2017: 19
- FWCI
- 31.99
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- intestinal stem cells, Paneth cells, glycolysis, lactate, oxidative phosphorylation, mitochondrial metabolism, p38 MAPK, reactive oxygen species signalling, organoid formation, cell differentiation
- MeSH terms
- Cell Self Renewal, Animals, Cell Differentiation, Glycolysis, Homeostasis, Intestinal Mucosa, Intestine, Small, Mitochondria, Organoids, Oxidative Phosphorylation, Stem Cells, Signal Transduction, Culture Media, Conditioned, Reactive Oxygen Species, Lactic Acid, Paneth Cells, Receptors, G-Protein-Coupled, p38 Mitogen-Activated Protein Kinases, Mice, Wnt3A Protein
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