TY - JOUR
T1 - Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium
AU - Pentinmikko, Nalle
AU - Iqbal, Sharif
AU - Mana, Miyeko
AU - Andersson, Simon
AU - Cognetta, Armand B.
AU - Suciu, Radu M.
AU - Roper, Jatin
AU - Luopajärvi, Kalle
AU - Markelin, Eino
AU - Gopalakrishnan, Swetha
AU - Smolander, Olli Pekka
AU - Naranjo, Santiago
AU - Saarinen, Tuure
AU - Juuti, Anne
AU - Pietiläinen, Kirsi
AU - Auvinen, Petri
AU - Ristimäki, Ari
AU - Gupta, Nitin
AU - Tammela, Tuomas
AU - Jacks, Tyler
AU - Sabatini, David M.
AU - Cravatt, Benjamin F.
AU - Yilmaz, Ömer H.
AU - Katajisto, Pekka
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/7/18
Y1 - 2019/7/18
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-019-1383-0
DO - 10.1038/s41586-019-1383-0
M3 - Article
C2 - 31292548
AN - SCOPUS:85068760534
SN - 0028-0836
VL - 571
SP - 398
EP - 402
JO - Nature
JF - Nature
IS - 7765
ER -