#paneth

Young Guts

In a rapidly ageing population, understanding how our cells change as we get older has never been more important. In the intestinal epithelium, the lining of our gut, stem cells divide to renew surrounding tissues, but this regeneration slows as we age. Using the ability of cultured intestinal stem cells (ISCs) to form clusters of cells, known as organoids (pictured), as a measure of their regenerative capacity, a recent study revealed that signals from neighbouring Paneth cells (in red) are responsible for this decline. Young ISCs surrounded by old Paneth cells show reduced organoid formation, as older Paneth cells secrete higher levels of Notum, an inhibitor of the critical Wnt signalling pathway required for stem cell activity. By contrast, blocking Notum boosts activity in old ISCs, suggesting that this could be a promising way to stimulate regeneration and thus help intestinal tissues to recover from damage, especially in older patients.

Written by Emmanuelle Briolat

Image from work by Nalle Pentinmikko and colleagues

Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland

Image copyright held by the original authors

Research published in Nature, July 2019

On April 29 the IAS in Princeton, New Jersey (https://www.ias.edu/), hosted the latest in a series of annual meetings titled “The Governor’s Conference on Effective Partnering in Cancer Research” (http://www.cinj.org/education/2014-governors-conference-effective-partnering-cancer-research). The meeting is organized by Arnie Levine, director of The Simons Center for Systems Biology’ (http://www.sns.ias.edu/csb).

The first talk by Hans Clevers from the Hubrecht Institute (http://www.hubrecht.eu/research/clevers/) described the fascinating discovery that Lgr5 (GPR49), a signaling protein in the Wnt pathway (http://www.rndsystems.com/Pathway.aspx?p=15489&r=15433) is a marker of many, if not most, adult and tumor stem cells. Clevers took an historical approach showing how the Austrian biologist Joseph Paneth (1857–1890), first reported these interesting large cells in the base of the intestinal crypts and then a narrow, slim cell that lies between each Paneth cell. Bringing us up to date Clevers showed how the narrow slim cells are in fact Lgr5 positive stem cells supported by factors such as EGF, TGF-alpha, Wnt-3 and the Notch ligand DII4 secreted by the Paneth cells. He showed how it was possible to isolate a single Lgr5+ cell and grow it clonally. In 3-D matrigel culture this cell goes on to produce what is essentially a miniature gut, a small vesicular body budding structures that are similar to villi. The growth and differentiation of these structures, as in the gut in vivo, is regulated through Lgr5 by Wnt agonists (R-spondins) and stem cell-specific E3 ligases that downregulate Wnt receptors. Some very beautiful movies explaining the role of Lgr5 in gut epithelium differentiation, gut tumor formation and in stem cells in other locations, such as the liver, can be found here, http://www.hubrecht.eu/research/clevers/research.html.

So why is all this medically important? The single mantra ‘follow the money’ is an excellent place to begin rooting out the causes of corruption in society. We can invent a similar mantra, ‘follow the pathway’ for understanding cancer. Understanding the Wnt pathway may lead us to identify targets that are amenable to treatment, perhaps through chemical synthesis of new Lgr5 ligands – drugs that correct aberrations in downstream functioning of the Wnt5 pathway. One such aberration is already well known. The most common mutation in colon cancer is inactivation of APC, a component of the complex of proteins that downregulate the Wnt pathway.