Letter | Published:

Interplay between metabolic identities in the intestinal crypt supports stem cell function

Nature volume 543, pages 424427 (16 March 2017) | Download Citation


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 crypt1. 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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This work was financially supported by CGC.nl (M.J.R.-C., H.J.S.), Utrecht Life Sciences (M.M.), Dutch Cancer Society ((KWF), EMCR 2012-5473 (M.S.), and UU 2013-6070 (K.C.O.)) and from the Netherlands Institute of Regenerative Medicine (R.F.). We thank H. Bos, T. Dansen and S. van Mil for helpful discussions and proofreading; F. de Sauvage (Genentech) for providing DTR–LGR5–GFP mice; T. Dick (DKFZ) for mtGrx1–roGFP and I. Verlaan (UMC Utrecht) for R-spondin/Wnt3a-conditioned medium.

Author information


  1. Molecular Cancer Research, Center Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584CG Utrecht, The Netherlands

    • Maria J. Rodríguez-Colman
    • , Maaike Meerlo
    • , Edwin Stigter
    • , Marten Hornsveld
    • , Koen C. Oost
    • , Hugo J. Snippert
    •  & Boudewijn M. T. Burgering
  2. Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

    • Matthias Schewe
    • , Andrea Sacchetti
    •  & Riccardo Fodde
  3. Department of Genetics and Center for Molecular Medicine, Lundlaan 6, 3584 EA Utrecht, The Netherlands

    • Johan Gerrits
    • , Mia Pras-Raves
    •  & Nanda Verhoeven-Duif


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M.J.R.-C. and B.M.T.B. conceived the project, designed and performed experiments and wrote the manuscript; M.S. designed and performed organoid reconstitution experiments; M.M. performed experiments; E.S. and J.G. performed metabolic measurements. M.P.-R. and N.V.-D. performed metabolic data analysis. A.S. performed FACS of intestinal cells. M.H. performed p38 IHC. K.C.O. and H.J.S. provided organoid cultures, and H.J.S. co-wrote the manuscript. R.F. designed experiments and co-wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Boudewijn M. T. Burgering.

Reviewer Information Nature thanks T. Sato, A. Schulze and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data

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  1. 1.

    Supplementary Figure 1

    This file contains full scan images of western blots used for Extended Data 4a and b. Molecular weight markers are indicated; pp38 (phospho-p38) and p38. Dashed lines indicated cropped areas shown in Extended Data 4a and b.

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