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

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  • Ömer H. Yilmaz

    (Massachusetts General Hospital and Harvard Medical School
    Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Pekka Katajisto

    (Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Dudley W. Lamming

    (Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Yetis Gültekin

    (Massachusetts General Hospital and Harvard Medical School
    Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Khristian E. Bauer-Rowe

    (Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Shomit Sengupta

    (Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Kivanc Birsoy

    (Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Abdulmetin Dursun

    (Massachusetts General Hospital and Harvard Medical School)

  • V. Onur Yilmaz

    (Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Martin Selig

    (Massachusetts General Hospital and Harvard Medical School)

  • G. Petur Nielsen

    (Massachusetts General Hospital and Harvard Medical School)

  • Mari Mino-Kenudson

    (Massachusetts General Hospital and Harvard Medical School)

  • Lawrence R. Zukerberg

    (Massachusetts General Hospital and Harvard Medical School)

  • Atul K. Bhan

    (Massachusetts General Hospital and Harvard Medical School)

  • Vikram Deshpande

    (Massachusetts General Hospital and Harvard Medical School)

  • David M. Sabatini

    (Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT)

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.

Suggested Citation

  • Ömer H. Yilmaz & Pekka Katajisto & Dudley W. Lamming & Yetis Gültekin & Khristian E. Bauer-Rowe & Shomit Sengupta & Kivanc Birsoy & Abdulmetin Dursun & V. Onur Yilmaz & Martin Selig & G. Petur Nielsen, 2012. "mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake," Nature, Nature, vol. 486(7404), pages 490-495, June.
    • Handle: RePEc:nat:nature:v:486:y:2012:i:7404:d:10.1038_nature11163
    DOI: 10.1038/nature11163
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    Cited by:

    1. Joana Silva & Ferhat Alkan & Sofia Ramalho & Goda Snieckute & Stefan Prekovic & Ana Krotenberg Garcia & Santiago Hernández-Pérez & Rob Kammen & Danielle Barnum & Liesbeth Hoekman & Maarten Altelaar & , 2022. "Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Ozren Stojanović & Jordi Altirriba & Dorothée Rigo & Martina Spiljar & Emilien Evrard & Benedek Roska & Salvatore Fabbiano & Nicola Zamboni & Pierre Maechler & Françoise Rohner-Jeanrenaud & Mirko Traj, 2021. "Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Shuting Li & Chia-Wen Lu & Elia C. Diem & Wang Li & Melanie Guderian & Marc Lindenberg & Friederike Kruse & Manuela Buettner & Stefan Floess & Markus R. Winny & Robert Geffers & Hans-Hermann Richnow &, 2022. "Acetyl-CoA-Carboxylase 1-mediated de novo fatty acid synthesis sustains Lgr5+ intestinal stem cell function," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Christian F. Christensen & Quentin Laurichesse & Rihab Loudhaief & Julien Colombani & Ditte S. Andersen, 2024. "Drosophila activins adapt gut size to food intake and promote regenerative growth," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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