Buissant des Amorie Julian R, Betjes Max A, Bernink Jochem H, Hageman Joris H, Geurts Veerle E, Begthel Harry, Laskaris Dimitrios, Heinz Maria C, Jordens Ingrid, Vinck Tiba, Houtekamer Ronja M, Verlaan-Klink Ingrid, Brunner Sascha R, van Rheenen Jacco, Gloerich Martijn, Clevers Hans, Tans Sander J, van Zon Jeroen S, Snippert Hugo J G
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Oncode Institute, Utrecht, The Netherlands.
Nat Commun. 2025 Jul 22;16(1):6765. doi: 10.1038/s41467-025-61878-9.
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.
肠道簇状细胞是上皮哨兵，在检测到寄生虫衍生化合物时触发宿主防御。虽然它们是炎症驱动的肠道疾病免疫调节治疗的有效靶点，但其功能和分化仍知之甚少。在这里，我们揭示了小鼠和人类中先前描述的簇状细胞-1和簇状细胞-2亚型之间的共同中间转录组。在类器官中进行簇状细胞亚型特异性报告基因敲入显示，这两种亚型反映了簇状细胞谱系中连续的有丝分裂后成熟阶段。用白细胞介素-4和13进行体外刺激足以促进新的Nrep+簇状细胞-1的产生，这些细胞由簇状前体细胞（tuft-p）产生。随后，需要隐窝-绒毛信号梯度（如骨形态发生蛋白）和胆碱能信号的变化来促进向Chat+簇状细胞-2表型的成熟。在功能上，我们发现化学感应能力在成熟过程中增强。我们的簇状细胞亚型特异性报告基因和类器官中优化的分化策略为研究免疫相关的簇状细胞亚型及其独特的化学感应特性提供了一个平台。
