Tuft Cells: Context- and Tissue-Specific Programming for a Conserved Cell Lineage

Kotas, Maya E.; O’Leary, Claire E.; Locksley, Richard M.

doi:10.1146/annurev-pathol-042320-112212

Cited by 15 publications

(30 citation statements)

References 145 publications

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“…In addition to the intestine, tuft cells have been identified in the lung, trachea, esophagus, stomach, thymus, pancreas, and biliary tract, and contribute to airway hypersensitivity. [42][43][44][45][46][47][48] Interestingly, HDAC3 is expressed ubiquitously, and butyrate levels at extra-intestinal sites reflect microbiota colonization. Thus, it is plausible that butyrate regulation of HDAC3 may control tuft cell-dependent immune responses at distant tissue sites as well.…”

Section: Discussionmentioning

confidence: 99%

Microbiota epigenetically direct tuft cell differentiation to control type 2 immunity

Eshleman¹,

Rice²,

Potter

et al. 2023

Preprint

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SUMMARYAllergy and anti-helminth immunity are driven by type 2 responses in mucosal tissues. Tuft cells are key regulators of type 2 immunity, however the factors that control these cells remain poorly understood. Here we find that butyrate-producing commensal bacteria decrease tuft cells in the intestine. Butyrate suppression of tuft cells required the epigenetic modifying enzyme histone deacetylase 3 (HDAC3), suggesting that HDAC3 may promote tuft cell-dependent immunity. Consistent with this, epithelial-intrinsic HDAC3 actively regulated tuft cell expansionin vivoand was required to induce type 2 immune responses during helminth infection. Interestingly, butyrate epigenetically restricted stem cell differentiation into tuft cells, and inhibition of HDAC3 in adult mice and human intestinal organoids was sufficient to block tuft cell expansion. Collectively, these data reveal an epigenetic pathway in stem cells that directs tuft cell differentiation, and highlight a new level of regulation through which commensal bacteria calibrate intestinal immunity.

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Section: Discussionmentioning

confidence: 99%

Microbiota epigenetically direct tuft cell differentiation to control type 2 immunity

Eshleman¹,

Rice²,

Potter

et al. 2023

Preprint

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“…The copyright holder for this preprint this version posted April 14, 2023. ; https://doi.org/10.1101/2023.04.14.536701 doi: bioRxiv preprint which would support their being Merkel cells. Alternatively, other scRNA-seq studies in mouse and human have shown that Hmx2 is expressed by tuft (brush) cells in gut and airway epithelia (Haber et al, 2017;Deprez et al, 2020), so it is possible the Hmx2-expressing skin cells in paddlefish are chemosensory epithelial cells, like tuft cells (Kotas et al, 2023).…”

Section: Mechanosensory-restricted Lateral Line Expression Of Hmx2 Is...mentioning

confidence: 99%

Identification of multiple transcription factor genes potentially involved in the development of electrosensory versus mechanosensory lateral line organs

Minařík

Modrell

Gillis

et al. 2023

Preprint

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In electroreceptive jawed vertebrates, embryonic lateral line placodes give rise to electrosensory ampullary organs as well as mechanosensory neuromasts. Previous reports of shared gene expression suggest that conserved mechanisms underlie electroreceptor and mechanosensory hair cell development and that electroreceptors evolved as a transcriptionally related 'sister cell type' to hair cells. We previously identified only one transcription factor gene, Neurod4, as ampullary organ-restricted in the developing lateral line system of a chondrostean ray-finned fish, the Mississippi paddlefish (Polyodon spathula). The other 16 transcription factor genes we previously validated in paddlefish were expressed in both ampullary organs and neuromasts. Here, we used our published lateral line organ-enriched gene-set (arising from differential bulk RNA-seq in late-larval paddlefish), together with a candidate gene approach, to identify 23 transcription factor genes expressed in the developing lateral line system of a more experimentally tractable chondrostean, the sterlet (Acipenser ruthenus, a small sturgeon), and/or that of paddlefish. Twelve are expressed in both ampullary organs and neuromasts, consistent with conservation of molecular mechanisms. Six are novel electrosensory-restricted transcription factor genes (Irx5, Satb2, Insm1, Sp5, MafA and Rorc), and five are the first-reported mechanosensory-restricted transcription factor genes (Foxg1, Sox8, Isl1, Hmx2 and Rorb). However, as previously reported, Sox8 is expressed in ampullary organs as well as neuromasts in a shark (Scyliorhinus canicula), suggesting the existence of lineage-specific differences between cartilaginous and ray-finned fishes. Overall, our results support the hypothesis that ampullary organs and neuromasts develop via largely conserved transcriptional mechanisms, and identify multiple transcription factors potentially involved in the formation of electrosensory versus mechanosensory lateral line organs.

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“…Tuft cells are solitary chemosensory cells found throughout epithelia of different organs (reviewed in [1]). Their numbers can increase dramatically upon infection, injury, or disease.…”

Section: Introductionmentioning

confidence: 99%

“…Expression of taste receptors and the succinate receptor 1 (SUCNR1) on tuft cells enables them to detect environmental changes in metabolites [7,8]. They are also characterized by expression of signal transduction genes characteristic for taste buds [1]. Activation of taste/chemosensory receptors on tuft cells transduces environmental signals to other effector systems.…”

Section: Introductionmentioning

confidence: 99%

“…The most studied effector function is activation of type 2 immunity through secretion of interleukin (IL)-25 that activates type 2 innate lymphoid cells (ILC2s), leading to secretion of IL-13 and other cytokines [3,9,10]. Furthermore, tuft cells express enzymes required for bioactive lipid synthesis, best characterized for production of prostaglandins, leukotrienes [1].…”

Section: Introductionmentioning

confidence: 99%

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Appearance of tuft cells during prostate cancer progression

et al. 2023

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Tuft cells are chemosensory epithelial cells that increase in number following infection or injury to robustly activate the innate immune response to alleviate or promote disease. Recent studies of castration resistant prostate cancer and its subtype, neuroendocrine prostate cancer, revealed Pou2f3+ populations in mouse models. The transcription factor Pou2f3 is a master regulator of the tuft cell lineage. We show that tuft cells are upregulated early during prostate cancer development, and their numbers increase with progression. Cancer-associated tuft cells in the mouse prostate express DCLK1, COX1, COX2, while human tuft cells express COX1. Mouse and human tuft cells exhibit strong activation of signaling pathways including EGFR and SRC-family kinases. While DCLK1 is a mouse tuft cell marker, it is not present in human prostate tuft cells. Tuft cells that appear in mouse models of prostate cancer display genotype-specific tuft cell gene expression signatures. Using bioinformatic analysis tools and publicly available datasets, we characterized prostate tuft cells in aggressive disease and highlighted differences between tuft cell populations. Our findings indicate that tuft cells contribute to the prostate cancer microenvironment and may promote development of more advanced disease. Further research is needed to understand contributions of tuft cells to prostate cancer progression.

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Tuft Cells: Context- and Tissue-Specific Programming for a Conserved Cell Lineage

Cited by 15 publications

References 145 publications

Microbiota epigenetically direct tuft cell differentiation to control type 2 immunity

Microbiota epigenetically direct tuft cell differentiation to control type 2 immunity

Identification of multiple transcription factor genes potentially involved in the development of electrosensory versus mechanosensory lateral line organs

Appearance of tuft cells during prostate cancer progression

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