Notum enzyme inhibited for better intestinal health

University of Helsinki researchers have discovered that the regenerative ability of intestinal epithelium (like skin cells) decreases as we age. Targeting of the enzyme Notum known to inhibit stem cell maintaining signaling restores regeneration in an aged intestine. Learning this may not only open ways to alleviate age-related gastrointestinal problems but also reduce the side-effects of cancer treatments, as well as healthcare costs in an aging society.

This study highlights the importance of cellular interactions. Alterations inside one cell resulted in secretion of an aging factor that can be targeted with drugs, providing multiple attractive points for interventions

Principal investigator Pekka Katajisto, Associate Professor at the University of Helsinki and Karolinska Institutet

Paneth cells sending us mixed signals

The age-induced decrease in tissue renewal makes finding the dosage for many common drugs challenging. Targeting Notum might present a way to increase the therapeutic window and support recovery in societies with an aging population. Researchers believe that as well as directly targeting Notum with medication, combating the enzyme might also be possible through lifestyle choices, like diet, and so improve tissue renewal and repair.

Using organoid culture methods, researchers understood that poor function of tissue repairing stem cells in an old intestine was because of unusual signals from the surrounding cells, called Paneth cells.

Modern techniques allowed us to examine tissue maintenance at a single-cell level and revealed which cell types contribute to the decline in tissue function. We were surprised to find that even young stem cells lost their capacity to renew tissue when placed next to old neighbors

Lead author, Ph.D. candidate Nalle Pentinmikko from the University of Helsinki

Wnt-signaling pathway blocked by Notum

Ordinarily, the intestinal epithelium is renewed by stem cells that rely on activity from the Wnt-signaling pathway (multiplication and restoration). Nearby cells produce molecules that activate this pathway. The study shows that during aging, Paneth cells begin to secrete (produce) the Wnt-inhibitor called Notum. Notum enzymatically inactivates Wnt-ligands in the stem cell niche, decreasing the regenerative potential of intestinal stem cells. However, pharmacologic inhibition of Notum renewed stem cell activity and improved recovery after chemotherapy with a drug known to cause severe side-effects in the gut.

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The writer of the article:

Ross Uren

Repair of aged tissue can be enhanced by inhibiting signals from neighbouring cells | University of Helsinki
Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium | Nature

Photo by Double–M on / CC BY


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