Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium

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, Santiago Naranjo, Tuure Saarinen, Anne Juuti, Kirsi Pietiläinen, Petri Auvinen, Ari Ristimäki, Nitin Gupta, Tuomas Tammela, Tyler Jacks, David M. Sabatini, Benjamin F. Cravatt, Ömer H. Yilmaz and Pekka Katajisto ()
Additional contact information
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
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
David M. Sabatini: The David H. Koch Institute for Integrative Cancer Research at MIT, 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

Nature, 2019, vol. 571, issue 7765, 398-402

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1383-0

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