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Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium

Author

Listed:
  • Nalle Pentinmikko

    (University of Helsinki)

  • Sharif Iqbal

    (University of Helsinki)

  • Miyeko Mana

    (The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT)

  • Simon Andersson

    (University of Helsinki)

  • Armand B. Cognetta

    (The Scripps Research Institute)

  • Radu M. Suciu

    (The Scripps Research Institute)

  • Jatin Roper

    (Division of Gastroenterology, Duke University)

  • Kalle Luopajärvi

    (University of Helsinki)

  • Eino Markelin

    (University of Helsinki)

  • Swetha Gopalakrishnan

    (University of Helsinki)

  • Olli-Pekka Smolander

    (University of Helsinki)

  • Santiago Naranjo

    (The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT)

  • Tuure Saarinen

    (University of Helsinki
    Abdominal Center, Department of Gastrointestinal Surgery, Helsinki University Hospital)

  • Anne Juuti

    (Abdominal Center, Department of Gastrointestinal Surgery, Helsinki University Hospital)

  • Kirsi Pietiläinen

    (University of Helsinki)

  • Petri Auvinen

    (University of Helsinki)

  • Ari Ristimäki

    (University of Helsinki and Helsinki University Hospital)

  • Nitin Gupta

    (Atlanta Gastroenterology Associates)

  • Tuomas Tammela

    (Memorial Sloan Kettering Cancer Center)

  • Tyler Jacks

    (The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT
    MIT)

  • David M. Sabatini

    (The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT
    MIT
    Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT)

  • Benjamin F. Cravatt

    (The Scripps Research Institute)

  • Ömer H. Yilmaz

    (The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT)

  • Pekka Katajisto

    (University of Helsinki
    University of Helsinki
    Karolinska Institutet)

Abstract

A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche1,2. Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor α (PPAR-α)3, and lowered PPAR-α activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.

Suggested Citation

  • Nalle Pentinmikko & Sharif Iqbal & Miyeko Mana & Simon Andersson & Armand B. Cognetta & Radu M. Suciu & Jatin Roper & Kalle Luopajärvi & Eino Markelin & Swetha Gopalakrishnan & Olli-Pekka Smolander & , 2019. "Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium," Nature, Nature, vol. 571(7765), pages 398-402, July.
    • Handle: RePEc:nat:nature:v:571:y:2019:i:7765:d:10.1038_s41586-019-1383-0
    DOI: 10.1038/s41586-019-1383-0
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    Cited by:

    1. Eun-Jung Kang & Jae-Hoon Kim & Young Eun Kim & Hana Lee & Kwang Bo Jung & Dong-Ho Chang & Youngjin Lee & Shinhye Park & Eun-Young Lee & Eun-Ji Lee & Ho Bum Kang & Moon-Young Rhyoo & Seungwoo Seo & Soh, 2024. "The secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Omid Omrani & Anna Krepelova & Seyed Mohammad Mahdi Rasa & Dovydas Sirvinskas & Jing Lu & Francesco Annunziata & George Garside & Seerat Bajwa & Susanne Reinhardt & Lisa Adam & Sandra Käppel & Nadia D, 2023. "IFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Jina Yun & Simon Hansen & Otto Morris & David T. Madden & Clare Peters Libeu & Arjun J. Kumar & Cameron Wehrfritz & Aaron H. Nile & Yingnan Zhang & Lijuan Zhou & Yuxin Liang & Zora Modrusan & Michelle, 2023. "Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Yongqiang Zheng & Kai Yu & Jin-Fei Lin & Zhuoran Liang & Qingfeng Zhang & Junteng Li & Qi-Nian Wu & Cai-Yun He & Mei Lin & Qi Zhao & Zhi-Xiang Zuo & Huai-Qiang Ju & Rui-Hua Xu & Ze-Xian Liu, 2025. "Deep learning prioritizes cancer mutations that alter protein nucleocytoplasmic shuttling to drive tumorigenesis," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    5. Liang Yang & Zifeng Ruan & Xiaobing Lin & Hao Wang & Yanmin Xin & Haite Tang & Zhijuan Hu & Yunhao Zhou & Yi Wu & Junwei Wang & Dajiang Qin & Gang Lu & Kerry M. Loomes & Wai-Yee Chan & Xingguo Liu, 2024. "NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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