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Regenerating the Aged and Damaged Intestine by Saying “No” to Notum

Review of “Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium” from Nature by Stuart P. Atkinson

A Paneth cell-containing niche supports the active cycling of intestinal stem cells (ISCs) [1, 2]; however, increased levels of complications observed in the gastrointestinal system with age suggest a reduction in both ISC activity and stem cell niche function. Fascinatingly, a recent Nature study by a team led by Pekka Katajisto (University of Helsinki, Helsinki, Finland) confirmed this hypothesis and established the production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells as a crucial factor in the reduced regenerative potential of the intestinal epithelium that functions by targeting ISC function [3]. However, Pentinmikko et al. also highlight the pharmacological inhibition of Notum as a potentially effective means to enhance the regenerative capacity of aged ISCs and even promote intestinal recovery from chemotherapy-induced damage. 

Can we regenerate the aged and damaged intestine by saying No to Notum?

Through the generation and evaluation of organoids formed from ISC-containing epithelial crypts, the authors confirmed the age-induced reduction in intestinal regeneration and ISC function; older specimens displayed a reduction in the organoid-forming capacity of colonic crypts when compared to younger samples. The results suggested that alterations intrinsic to the intestinal epithelium prompted the decline in regeneration, and the authors found evidence for a significant loss in ISCs but a significant increase in the Paneth cells during the aging process.

Focusing on these ISC niche cells, the authors noted the significant overexpression of Notum, which disengages Wnt ligands from receptors and reduces Wnt activity locally during development, in older Paneth cells. Interestingly, the addition of recombinant Notum diminished the ability of single ISCs to form clonal spheroids in culture, suggesting that Notum secretion by Paneth cells reduces intestinal regeneration during aging through the ever-increasing inhibition of Wnt-signaling in ISCs. As Wnt signals produced by niche cells act as stemness-maintaining factors for ISCs [4], the reduction in Wnt signaling via Notum may prompt the loss of ISC function.

Mechanistically, the study found evidence that an increase in the activity of the mammalian target of rapamycin complex 1 (mTORC1) in Paneth cells during aging led to the inhibition of peroxisome proliferator-activated receptor α (PPAR-α) activity via transcriptional downregulation of gene expression, which itself prompted the increased expression of Notum. The authors note that previous studies have demonstrated a link between mTOR signaling and aging [5] and that mTORC1 modulates the activity of ISCs via the Paneth cell niche in response to calorie intake [6].

The authors hypothesized that interfering in this pathway may provide a means to regenerate the aged or damaged intestinal epithelium, and their final studies established that Notum loss or Wnt supplementation counteracted the loss of function in intestinal organoids. Additionally, treatment with a small-molecule inhibitor of Notum (ABC9925) enhanced the regenerative capacity of aged ISCs and promoted recovery from chemotherapy-induced damage in mice.

While these exciting new findings highlight the relative importance of niche regulated Wnt signals in the stemness of ISCs and demonstrate a link between aging-associated metabolic changes and tissue maintenance, they also point towards a safe and effective means to treat gastrointestinal complications and reduce the side-effects of chemotherapeutic agents in both young and old patients.

For more on intestinal stem cells, the importance of stem cell niche, and how saying “No” to Notum may promote the regeneration of the aged and damaged intestine, stay tuned to the Stem Cells Portal!


  1. Barker N, van Es JH, Kuipers J, et al., Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007;449:1003.
  2. Sato T, van Es JH, Snippert HJ, et al., Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 2010;469:415.
  3. Pentinmikko N, Iqbal S, Mana M, et al., Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium. Nature 2019;571:398-402.
  4. Clevers H, The Intestinal Crypt, A Prototype Stem Cell Compartment. Cell 2013;154:274-284.
  5. Sengupta S, Peterson TR, Laplante M, et al., mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010;468:1100-1104.
  6. Yilmaz ÖH, Katajisto P, Lamming DW, et al., mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 2012;486:490-495.