| Literature DB >> 31292548 |
Sharif Iqbal1, Miyeko Mana2, Nalle Pentinmikko1, Simon Andersson1, Armand B Cognetta3, Radu M Suciu3, Jatin Roper4, Kalle Luopajärvi1, Eino Markelin1, Swetha Gopalakrishnan1, Olli-Pekka Smolander1, Santiago Naranjo2, Tuure Saarinen5,6, Anne Juuti6, Kirsi Pietiläinen5, Petri Auvinen1, Ari Ristimäki7, Nitin Gupta8, Tuomas Tammela9, Tyler Jacks2,10, David M Sabatini2,10,11, Benjamin F Cravatt3, Ömer H Yilmaz2, Pekka Katajisto12,13,14.
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.Entities:
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Year: 2019 PMID： 31292548 PMCID： PMC8151802 DOI： 10.1038/s41586-019-1383-0
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962