Journal Article

Paneth cell produced Notum attenuates regeneration of aged intestinal epithelium

Smolander, Olli-Pekka, Pietiläinen, Kirsi, Tammela, Tuomas, Jacks, Tyler, Cravatt, Benjamin F., Gopalakrishnan, Swetha, Andersson, Simon, Cognetta, Armand B., Naranjo, Santiago, Auvinen, Petri, Saarinen, Tuure, Katajisto, Pekka, Roper, Jatin, Sabatini, David M., Gupta, Nitin, Pentinmikko, Nalle, Mana, Miyeko, Markelin, Eino, Iqbal, Sharif, Juuti, Anne, Ristimäki, Ari, Yilmaz, Ömer H., Luopajärvi, Kalle, Suciu, Radu M.

2019

Overview

A decline in stem cell function impairs tissue regeneration during aging, but the role of the stem cell supporting niche in aging is not well understood. The small intestine is maintained by actively cycling intestinal stem cells (ISCs) 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 due to defects in both stem cells and their niche. The functional decline was caused by decrease in stemness maintaining Wnt signalling due to production of an extracellular Wnt-inhibitor, Notum, in aged Paneth cells. Mechanistically, high mTORC1 activity in old Paneth cells inhibits PPARa activity3 and lowered PPARa increased Notum expression. Genetic targeting of Notum or Wnt-supplementation restored function of old intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of old stem cells and promoted recovery from chemotherapy induced damage. Our results reveal an unappreciated role for the stem cell niche in aging and demonstrate that targeting of Notum can promote regeneration of old tissues.