Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion

Johan H. van Es, Kay Wiebrands, Carmen López-Iglesias, Marc van de Wetering, Laura Zeinstra, Maaike van den Born, Jeroen Korving, Nobuo Sasaki, Peter J. Peters, Alexander van Oudenaarden, and Hans Clevers

Published: 26/12/2019


Cycling intestinal Lgr5+ stem cells are intermingled with their terminally differentiated Paneth cell daughters at crypt bottoms. Paneth cells provide multiple secreted (e.g., Wnt, EGF) as well as surface-bound (Notch ligand) niche signals. Here we show that ablation of Paneth cells in mice, using a diphtheria toxin receptor gene inserted into the P-lysozyme locus, does not affect the maintenance of Lgr5+ stem cells. Flow cytometry, single-cell sequencing, and histological analysis showed that the ablated Paneth cells are replaced by enteroendocrine and tuft cells. As these cells physically occupy Paneth cell positions between Lgr5 stem cells, they serve as an alternative source of Notch signals, which are essential for Lgr5+ stem cell maintenance. Our combined in vivo results underscore the adaptive flexibility of the intestine in maintaining normal tissue homeostasis.

Full Access Link: Proceedings of the National Academy of Sciences of the United States of America