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mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake

Abstract

How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.

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Figure 1: Calorie restriction augments the capacity of Paneth cells to boost ISC function.
Figure 2: Nutritional regulation of mTORC1 in Paneth cells.
Figure 3: mTORC1 signalling in Paneth cells mediates the effects of calorie restriction on ISC function.
Figure 4: Calorie restriction enhances expression of Bst1 in Paneth cells, the product of which, cADPR, enhances ISC function.

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Gene Expression Omnibus

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Microarray data have been deposited in the GEO database under accession number GSE37209.

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Acknowledgements

This work was supported by the National Institutes of Health (CA103866 and CA129105 to D.M.S.), the Koch Institute (Initiator award to D.M.S.), Ellison Medical Foundation (D.M.S.), the Warshaw Institute from the Massachusetts General Hospital (Ö.H.Y.), and the Center for the study of Inflammatory Bowel Disease from the Massachusetts General Hospital (Ö.H.Y. and D.M.S.), and fellowship support from the NCI (T32CA09216 to the Department of Pathology at the MGH to Ö.H.Y.), the Academy of Finland and the Foundations’ Post Doc Pool (P.K.), the NIH (1F32AG032833-01A1 to D.W.L.) and Jane Coffin Childs Medical Fund (K.B.). We thank P. Wisniewski and C. Araneo of the Whitehead flow cytometry core facility, the Whitehead Genome Technology Core and Bioinformatics and Research Computing, S. Holder for histology and help with special stains, K. Ottina for laboratory management, and A. Hutchins for animal husbandry and genotyping. D.M.S. is an investigator of the Howard Hughes Medical Institute.

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Ö.H.Y. and P.K. designed and performed all experiments and data analyses with input from D.M.S. S.S. generated the Rheb2 transgenic mice. D.W.L., K.B., V.D., A.K.B., M.M.-K. and L.R.Z. participated in design and interpretation of experiments. Y.G., V.O.Y., A.D. and K.E.B.-R. performed and interpreted all of the immunohistochemistry and in situ hybridization under the guidance of Ö.H.Y. M.S. and G.P.N. performed electron microscopy and helped with its interpretation. Ö.H.Y. wrote the paper with help from P.K. and D.M.S.

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Correspondence to David M. Sabatini.

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The authors declare no competing financial interests.

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Yilmaz, Ö., Katajisto, P., Lamming, D. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012). https://doi.org/10.1038/nature11163

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