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 E. Geurts, Harry Begthel, Dimitrios Laskaris, Maria C. Heinz, Ingrid Jordens, Tiba Vinck, Ronja M. Houtekamer, Ingrid Verlaan-Klink, Sascha R. Brunner, Jacco Rheenen, Martijn Gloerich, Hans Clevers, Sander J. Tans, Jeroen S. Zon and Hugo J. G. Snippert ()
Additional contact information
Julian R. Buissant des Amorie: University Medical Center Utrecht
Max A. Betjes: AMOLF
Jochem H. Bernink: Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht
Joris H. Hageman: University Medical Center Utrecht
Veerle E. Geurts: Oncode Institute
Harry Begthel: Oncode Institute
Dimitrios Laskaris: Oncode Institute
Maria C. Heinz: University Medical Center Utrecht
Ingrid Jordens: University Medical Center Utrecht
Tiba Vinck: University Medical Center Utrecht
Ronja M. Houtekamer: University Medical Center Utrecht
Ingrid Verlaan-Klink: University Medical Center Utrecht
Sascha R. Brunner: University Medical Center Utrecht
Jacco Rheenen: Oncode Institute
Martijn Gloerich: University Medical Center Utrecht
Hans Clevers: Oncode Institute
Sander J. Tans: AMOLF
Jeroen S. Zon: AMOLF
Hugo J. G. Snippert: University Medical Center Utrecht

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61878-9

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