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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月22日

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  • 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 van Rheenen,
  • Martijn Gloerich,
  • Hans Clevers,
  • Sander J. Tans,
  • Jeroen S. van Zon,
  • Hugo J. G. Snippert

摘要

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.