Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients

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DOI http://dx.doi.org/10.1038/s41467-025-61878-9
Reference J.R. Buissant des Amorie, M.A. Betjes, J.H. Bernink, J.H. Hageman, V.E. Geurts, H. Begthel, D. Laskaris, M.C. Heinz, I. Jordens, T. Vinck, R.M. Houtekamer, I. Verlaan-Klink, S.R. Brunner, J. van Rheenen, M. Gloerich, H. Clevers, S.J. Tans, J.S. van Zon and H.J.G. Snippert, Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients, Nat. Commun. 16, (1), 6765 : 1-18 (2025)
Groups Biophysics, Quantitative Developmental Biology

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.