Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients
Julian R. Buissant des Amorie (Oncode Institute, University Medical Centre Utrecht)
Max A. Betjes (AMOLF Institute for Atomic and Molecular Physics)
Jochem H. Bernink (Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Centre Utrecht)
Joris H. Hageman ( University Medical Centre Utrecht, Oncode Institute)
Veerle E. Geurts (Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Centre Utrecht)
Harry Begthel (Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), Hubrecht Institute, University Medical Centre Utrecht)
Dimitrios Laskaris (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Sander J. Tans (Kavli institute of nanoscience Delft, TU Delft - BN/Sander Tans Lab)
Hugo J. G. Snippert ( University Medical Centre Utrecht, Oncode Institute)
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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.
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