Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients
Julian R. Buissant des Amorie, Max A. Betjes, Jochem H. Bernink, Joris H. Hageman, Veerle Geurts, Harry Begthel, Dimitrios Laskaris, Maria C. Heinz, Ingrid Jordens, Tiba Vinck, Ronja M. Houtekamer, Ingrid Verlaan-Klink, Sascha R. Brunner, Jacco van Rheenen, Martijn Gloerich, Hans Clevers, Sander J. Tans, Jeroen S. van Zon, Hugo J.G. Snippert
Abstract
Intestinal tuft cells are epithelial sentinels that trigger host defense upon detection of parasite-derived compounds. While they represent potent targets for immunomodulatory therapies in inflammation-driven intestinal diseases, their functioning and differentiation are poorly understood. Here, we reveal common intermediary transcriptomes among the previously described tuft-1 and tuft-2 subtypes in mouse and human. Tuft cell subtype-specific reporter knock-ins in organoids show that the two subtypes reflect successive post-mitotic maturation stages within the tuft cell lineage. In vitro stimulation with interleukin-4 and 13 is sufficient to fuel the generation of new Nrep+ tuft-1 cells, arising from tuft precursors (tuft-p). Subsequently, changes in crypt-villus signaling gradients, such as BMP, and cholinergic signaling, are required to advance maturation towards Chat+ tuft-2 phenotypes. Functionally, we find chemosensory capacity to increase during maturation. Our tuft subtype-specific reporters and optimized differentiation strategy in organoids provide a platform to study immune-related tuft cell subtypes and their unique chemosensory properties. Intestinal tuft cell subtypes represent successive stages of differentiation that is driven by crypt-villus signaling gradients. Here, the authors show that applying these gradients to organoids generates mature immune-related chemosensory tuft cells suitable for experimental studies.