Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients
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....
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61878-9 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Julian R. Buissant des Amorie |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bc363b1766af44ed9663a00dc862dba4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bc363b1766af44ed9663a00dc862dba42025-08-20T04:03:07ZengNature PortfolioNature Communications2041-17232025-07-0116111810.1038/s41467-025-61878-9Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradientsJulian R. Buissant des Amorie0Max A. Betjes1Jochem H. Bernink2Joris H. Hageman3Veerle E. Geurts4Harry Begthel5Dimitrios Laskaris6Maria C. Heinz7Ingrid Jordens8Tiba Vinck9Ronja M. Houtekamer10Ingrid Verlaan-Klink11Sascha R. Brunner12Jacco van Rheenen13Martijn Gloerich14Hans Clevers15Sander J. Tans16Jeroen S. van Zon17Hugo J. G. Snippert18Center for Molecular Medicine, University Medical Center UtrechtAMOLFHubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center UtrechtCenter for Molecular Medicine, University Medical Center UtrechtOncode InstituteOncode InstituteOncode InstituteCenter for Molecular Medicine, University Medical Center UtrechtCenter for Molecular Medicine, University Medical Center UtrechtCenter for Molecular Medicine, University Medical Center UtrechtCenter for Molecular Medicine, University Medical Center UtrechtCenter for Molecular Medicine, University Medical Center UtrechtCenter for Molecular Medicine, University Medical Center UtrechtOncode InstituteCenter for Molecular Medicine, University Medical Center UtrechtOncode InstituteAMOLFAMOLFCenter for Molecular Medicine, University Medical Center UtrechtAbstract 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.https://doi.org/10.1038/s41467-025-61878-9 |
| spellingShingle | 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 Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients Nature Communications |
| title | Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients |
| title_full | Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients |
| title_fullStr | Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients |
| title_full_unstemmed | Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients |
| title_short | Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients |
| title_sort | intestinal tuft cell subtypes represent successive stages of maturation driven by crypt villus signaling gradients |
| url | https://doi.org/10.1038/s41467-025-61878-9 |
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