Paneth cell produced Notum attenuates regeneration of aged intestinal epithelium
By Nalle Pentinmikko, Sharif Iqbal, Miyeko D. Mana, S. Andersson, Armand B. Cognetta Jr., Radu M. Suciu, Jatin Roper, Kalle Luopajärvi, Eino Markelin, S. Gopalakrishnan and 14 more. 2019
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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. Ageing-associated decline in intestinal stem cell function is mediated by increased Notum, a protein inhibitor of stemness-maintaining Wnt signalling, which is secreted by Paneth cells.
Subfields: Molecular Biology, Oncology, Physiology
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Citations in the corpus
- Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity (2023, positive): “ABC99 is a valuable research tool that has been used to investigate the link between inhibition of Notum activity with cellular regeneration in aged intestinal epithelium [11] and neurogenesis in the subventricular zone of the brain [12].”
- Single-Cell Profiling and SCOPE-Seq Reveal Lineage Dynamics of Adult Ventricular-Subventricular Zone Neurogenesis and NOTUM as a Key Regulator (2020, unknown): “Short-term systemic ABC99 administration showed no obvious adverse effects on animal health, as previously reported (Pentinmikko et al., 2019).”