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Tuft cell

Tuft cells are a rare and morphologically distinct population of chemosensory epithelial cells, first identified in the 1950s, that are characterized by their prominent apical tuft of densely packed microvilli and a unique cytoskeletal superstructure supported by actin filaments and cytospinules.^[1] These cells are primarily located in the mucosal epithelia of the gastrointestinal tract, respiratory airways, and other barrier tissues such as the thymus and pancreas, where they constitute less than 1% of epithelial cells and exhibit a short lifespan of approximately 7 days.^[1] Tuft cells originate from Lgr5-positive intestinal stem cells or secretory progenitors in the crypt-villus axis, differentiating postnatally around day 7 through regulation by transcription factors such as Pou2f3, Gfi1b, and Atoh1, with Notch and Wnt signaling pathways playing critical roles in fate determination.^[1] Key biomarkers include Dclk1 (doublecortin-like kinase 1), Trpm5 (transient receptor potential channel M5), and ChAT (choline acetyltransferase), which distinguish tuft cell subtypes, such as neuronal-like (expressing serotonin) and immunological variants.^[1] Recent studies have revealed heterogeneity among tuft cells, with subtypes representing successive maturation stages that respond to specific environmental cues via receptors like succinate receptor 1 (SUCNR1).^[2] Functionally, tuft cells serve as sentinels for luminal antigens, detecting metabolites (e.g., succinate from microbiota), protozoa, and helminths through chemosensory mechanisms involving taste-like receptors and TRPM5-dependent depolarization, leading to the release of effector molecules such as interleukin-25 (IL-25) and acetylcholine.^[1] This initiates a tuft cell-innate lymphoid cell type 2 (ILC2) circuit that amplifies type 2 immunity, promoting goblet cell hyperplasia, mucus production, and expulsion of parasites while modulating the gut microbiota composition. In the airways, tuft cells similarly drive allergic responses and host defense against viruses.^[3] Beyond immunity, tuft cells contribute to epithelial homeostasis and regeneration; notably, in humans, they exhibit stem-like properties, surviving irradiation and differentiating into other epithelial lineages to repair intestinal damage.^[4] Dysregulation of tuft cells is implicated in diseases, including inflammatory bowel disease (where reduced numbers correlate with colitis severity), colorectal cancer (with Dclk1-positive tuft cells acting as cancer stem cells), and obesity (via altered IL-25 signaling affecting energy balance).^[1] Emerging research highlights their potential as therapeutic targets for modulating mucosal immunity and tissue repair.

Overview and Discovery

Definition and Characteristics

Tuft cells are rare chemosensory epithelial cells found primarily at mucosal surfaces throughout the body, distinguished by their unique morphology featuring an apical tuft of densely packed microvilli that project into the lumen, often resembling a paintbrush or brush-like structure.^[5] These cells serve as intraepithelial sentinels, detecting environmental cues such as luminal stimuli in organs like the gastrointestinal and respiratory tracts.^[2] Key characteristics include the absence of cilia, setting them apart from other epithelial cell types, and the presence of prominent tubulin-based structures within their microvilli, where acetylated microtubules intertwine with actin filaments to form a robust cytoskeletal superstructure supporting the tuft.^[6]^[7] This organization enables tuft cells to function as specialized sensors without the motile or primary ciliary apparatus typical of ciliated epithelia. In relevant tissues, such as the intestinal epithelium, tuft cells typically constitute a small fraction of the epithelial population, comprising approximately 0.4–2% of cells under homeostatic conditions. Tuft cells exhibit evolutionary conservation across vertebrate species, appearing in diverse mucosal epithelia from fish to mammals, underscoring their fundamental role in epithelial sensory functions.^[8] This conservation highlights their classification as a distinct cell type, integral to tissue homeostasis and response to external perturbations.^[9]

Historical Discovery

The earliest observations of tuft cells trace back to the late 1920s, when Soviet microscopist A. Chlopkov identified unusual cylindrical cells featuring a prominent brush border in the intestinal epithelium of rodents during studies on goblet cell development. These cells were noted for their distinct morphology but were not yet recognized as a separate lineage, remaining overlooked amid the focus on more common epithelial types.^[10] A more detailed characterization emerged in 1956 through independent studies using electron microscopy. J.A.G. Rhodin and T. Dalhamn described these cells in the rat trachea as possessing a dense tuft of apical microvilli, coining the term "tuft cells" to reflect this striking feature, while O. Järvi and O. Keyriläinen simultaneously reported similar cells in the mouse glandular stomach. These findings established tuft cells as a rare epithelial population across mucosal surfaces, distinguished by their brush-like projections and cytoplasmic density.^[11] Throughout the 1970s and 1980s, advances in transmission and scanning electron microscopy further elucidated tuft cell ultrastructure, confirming their scarcity—typically comprising less than 1% of epithelial cells—and revealing their distribution in diverse organs, including the airways, gastrointestinal tract, and exocrine glands of rodents and other mammals. Studies highlighted features such as prominent Golgi apparatus, intermediate filaments, and tubulovesicular structures, solidifying their identity as a conserved but enigmatic cell type. The 2010s marked a shift toward molecular insights, with research linking tuft cell differentiation to the transcription factor ATOH1, essential for secretory lineage commitment in the intestinal epithelium, while distinguishing them from other cell types via unique markers like DCLK1 and TRPM5. This era also uncovered their chemosensory capabilities, including taste receptor expression and roles in detecting luminal stimuli, transforming tuft cells from morphological curiosities into recognized signaling hubs.^[12] In a pivotal 2024 study, Huang et al. demonstrated that human intestinal tuft cells serve as reserve stem cells, capable of proliferating in response to interleukin-4 and -13 signals to regenerate the epithelium following irradiation or injury, generating all major cell lineages in organoid models. This revelation underscores their regenerative potential, previously underappreciated in human contexts.^[4] Building on this, 2025 research further elucidated tuft cell regulation, revealing that the transcription factor Spi-B acts as a checkpoint to restrain tuft cell activation and intestinal type 2 immunity, while studies identified circadian fluctuations in tuft cell abundance, peaking at dusk in alignment with active phases.^[13]^[14]

Morphology

Ultrastructural Features

Tuft cells are distinguished by their prominent apical tuft, composed of numerous elongated microvilli that project into the lumen, typically numbering around 100 per cell as revealed by quantitative electron microscopy analyses. These microvilli, measuring approximately 0.2 μm in width and 2.3 μm in length, are densely packed and supported by parallel bundles of F-actin filaments crosslinked in a polarized, barbed-end-out configuration, with enrichment of actin-binding proteins such as advillin and fimbrin. An actomyosin belt is present at the junctional region, contributing to the structural rigidity and brush-border-like appearance of the tuft.^[15]^[16] A defining internal feature is the extensive tubulovesicular system, derived from the endoplasmic reticulum, which originates at the base of the microvilli and extends deeply through the cytoplasm toward the nucleus. This network consists of interconnected tubules and vesicles, facilitating membrane trafficking and observed to span much of the subapical domain in three-dimensional reconstructions. Complementing this, tuft cells contain dense core vesicles in the cytoplasm, specialized for the storage and secretion of mediators such as acetylcholine, which are released upon cellular activation.^[17]^[16]^[15] The cytoskeleton of tuft cells forms a robust superstructure that integrates these elements, featuring intermediate filaments such as cytokeratins 8 and 18 that provide additional support in the subapical region. Desmosomal attachments anchor tuft cells to adjacent epithelial cells, ensuring mechanical stability within the tissue. Notably, unlike many other epithelial cell types, tuft cells lack primary cilia, a feature confirmed through ultrastructural examinations that highlight their unique reliance on the microvillar tuft for luminal interactions.^[18]^[17]

Organ-Specific Variations

Tuft cells exhibit morphological adaptations tailored to the structural demands of their resident epithelia, with variations in shape, microvillar architecture, and intracellular networks reflecting tissue-specific constraints. While sharing core features such as an apical tuft of microvilli supported by actin bundles, these cells display distinct profiles across organs, including differences in overall height, surface area, and cytoskeletal organization.^[19] In the intestine, tuft cells adopt an elongated, fusiform or bottle-shaped morphology, measuring approximately 17–20 μm in height with a narrow apical surface of about 0.2 μm in width that widens to 7–13 μm at the nuclear region. Their apical domain features a prominent tuft of long, blunt microvilli extending roughly 2 μm into the lumen, anchored by approximately 100 core actin bundles each comprising around 100 hexagonally packed F-actin filaments, with lengths ranging from 5–12 μm. These bundles exhibit parallel, barbed-end-out polarity and interdigitate with microtubules in the subapical cytoplasm, forming a cytoskeletal superstructure that extends rootlets to the perinuclear region. An extensive tubulovesicular network permeates the apical cytoplasm, comprising electron-lucent vesicles without endocytic activity, alongside lateral cytospinules up to 3 μm long that contact adjacent cell nuclei. Recent ultrastructural analyses have highlighted this co-aligned actin-microtubule organization as a specialized adaptation for apical domain stability in the dynamic intestinal environment.^[20]^[19]^[16] Respiratory tract tuft cells, often termed brush cells, present a shorter, more cuboidal profile compared to their intestinal counterparts, with a height typically under 15 μm and a broader basal attachment suited to the pseudostratified airway epithelium. Their apical surface bears a dense array of prominent microvilli forming a brush-like tuft, though these are generally fewer in number and accompanied by reduced ciliary coverage relative to neighboring ciliated cells; the microvilli lack a terminal web and are supported by robust actin rootlets extending deeply into the cytoplasm. This configuration contrasts with the elongated protrusions of intestinal tuft cells, emphasizing a compact design for integration within the thinner respiratory mucosal layer.^[21]^[22] In the gallbladder and pancreatic ducts, tuft cells display a more flattened or irregular shape, with heights around 10–15 μm and reduced apical surface area, often appearing cuboidal or squat to align with the compact ductal architecture. They feature a prominent apical tuft of tall, thick microvilli extending into the lumen, with a tubulovesicular system present; these cells incorporate neurofilament bundles in their cytoskeleton, contributing to a more rigid, neuron-like structural framework. Such adaptations suit the static, bile-filled environment of these organs, where tuft cells cluster more densely than in other epithelia.^[23]^[24]^[25] Urethral tuft cells adopt a pear-shaped morphology, approximately 12–18 μm tall, with a pronounced apical tuft enriched in microvilli expressing bitter taste receptors, measuring 1–2 μm in length and densely packed to maximize surface exposure. These microvilli feature a specialized glycocalyx and are undergirded by actin filaments without extensive tubulovesicular networks, differing from the nutrient-oriented structures in the gut; the overall form tapers basally for efficient signaling within the transitional urethral epithelium.^[26]^[27]^[8]

Distribution

In Humans

Tuft cells are primarily distributed in the human gastrointestinal tract, spanning from the duodenum to the colon, where they constitute approximately 0.5% of the epithelial cells.^[28] These cells are enriched in the crypts of the small intestine and the surface epithelium of the large intestine, with cholinergic tuft cells localizing to both villi and crypts in these regions while being absent from the stomach.^[29] Tuft cells are also found in the pancreatic ducts.^[30] In the airways, tuft cells are present in the tracheal and bronchial epithelium, where they contribute to mucociliary clearance and innate immune regulation.^[31] They are also found in the genitourinary tract, including the urethra, acting as sentinels for microbial detection.^[32] Beyond these primary sites, tuft cells appear in the olfactory epithelium of the nasal mucosa, though at lower densities, and in the thymus, where they are rarer but involved in immune modulation.^[33]^[34] In humans, tuft cells in the duodenum express doublecortin-like kinase 1 (DCLK1), a marker associated with neuroendocrine-like functions, including chemosensation and potential roles in mucosal signaling.^[35]

Across Species

Tuft cells exhibit a high degree of conservation across mammalian species, with prominent abundance in the intestines and airways of rodents such as mice and rats, where they serve as key model systems for genetic and functional studies.^[36] In these rodents, tuft cells are distributed throughout the gastrointestinal epithelium, particularly in the small intestine, and in the respiratory tract, including the trachea and bronchi, facilitating investigations into their chemosensory roles via targeted genetic manipulations like knockout models.^[8] This conservation extends to other mammals, including dogs and non-human primates, though with variations in marker expression and density that highlight species-specific adaptations.^[8] Beyond mammals, tuft cells are present in lower vertebrates, including fish and amphibians, where they localize to gill and skin epithelia to support environmental sensing. In fish such as lampreys, tuft-like cells appear in gill tufts, contributing to ion regulation and chemosensory detection of water-borne cues.^[37] Similarly, in larval amphibians like Xenopus laevis, these cells are found in gill structures, aiding in osmoregulation and response to aquatic environmental changes.^[38] Their presence in these ectodermal and endodermal-derived epithelia underscores an evolutionary role in mucosal surveillance across vertebrates.^[8] In avian species, tuft cells are identified in both respiratory and digestive tracts, with notable presence in the bronchial epithelia of chickens, where brush-like variants—synonymous with tuft cells—occur scattered among other cell types. In the digestive system, single-cell analyses of chicken intestinal organoids reveal tuft cells alongside enterocytes and goblet cells, indicating their integration into the epithelial landscape.^[39] These cells show higher density in upper respiratory regions like the trachea compared to deeper lung structures, aligning with patterns observed in mammals.^[40] True tuft cell equivalents are limited in invertebrates, though certain sensory cells in nematodes exhibit analogous microvilli traits for chemosensory functions. Nematode amphidial neurons feature ciliated or microvilli-covered structures that detect environmental and host signals, sharing morphological similarities with the apical tufts of vertebrate tuft cells but lacking epithelial integration.^[41] This suggests convergent evolution in sensory adaptations rather than direct homology.^[8] Species-specific differences in tuft cell abundance are evident, particularly with higher numbers in herbivores such as sheep, where they expand markedly in response to intestinal parasites, reflecting adaptations to frequent helminth exposure in grazing environments.^[42] In contrast, omnivorous models like mice show more modest baseline densities, emphasizing how ecological pressures influence tuft cell populations for enhanced parasite vigilance in herbivorous mammals.^[43]

Development

Cellular Lineage and Differentiation

Tuft cells originate from multipotent endodermal progenitors in the gastrointestinal and respiratory epithelia, sharing a common secretory lineage with other epithelial cell types such as goblet and enteroendocrine cells.^[9] In the developing intestine, these progenitors give rise to tuft cells through a process dependent on the transcription factor ATOH1, which is required for their specification and differentiation into a distinct secretory subtype.^[44] ATOH1 promotes tuft cell commitment by activating downstream genes like DCLK1 and SOX9, while Neurog3, essential for enteroendocrine differentiation, is dispensable for tuft cells, underscoring their unique lineage branch.^[44] Notch signaling acts as an inhibitor of tuft cell differentiation, favoring columnar cell fates in progenitors through lateral inhibition mediated by Hes1, which represses secretory programs including those driven by ATOH1 or Gfi1b.^[45] In adult tissues, tuft cells are continuously generated from Lgr5+ stem cells in the intestinal crypts, with a turnover time of approximately 7 days, as determined by lineage tracing and labeling studies.^[44] This process is amplified by the IL-13/STAT6 signaling pathway, where IL-13, produced by immune cells, binds to receptors on stem cells to drive tuft cell specification and expansion via STAT6 activation, often resulting in hyperplasia.^[46] Recent findings demonstrate that subsets of mature tuft cells retain stem-like potential, serving as reserve cells that survive irradiation-induced damage (5-6 Gy) and regenerate the full epithelial lineage, including enterocytes and secretory cells, particularly when stimulated by IL-4/IL-13.^[4] Tuft cells emerge postnatally in the intestine, becoming detectable around 1-2 weeks after birth in mice, coinciding with microbial colonization and weaning.^[47] In the respiratory tract, they appear prenatally but undergo significant postnatal expansion, particularly post-weaning; recent single-cell studies have identified a highly replicating bipotent progenitor population in human airways that gives rise to either tuft cells or ionocytes.^[9]^[3] During infections, such as with helminths, tuft cell numbers increase rapidly through hyperplasia, peaking within 3-7 days via IL-13-driven differentiation from progenitors.

Molecular Markers and Identification

Tuft cells are primarily identified through a set of canonical molecular markers that distinguish them from other epithelial cell types. The most widely recognized include doublecortin-like kinase 1 (DCLK1), transient receptor potential channel M5 (TRPM5), and the transcription factor POU2F3. DCLK1 is a microtubule-associated kinase expressed in the apical cytoplasm of tuft cells, serving as a hallmark for their identification across intestinal and airway epithelia.^[48] TRPM5, a cation channel involved in taste signaling, is consistently upregulated in tuft cells and contributes to their chemosensory properties.^[2] POU2F3 acts as a lineage-specifying transcription factor essential for tuft cell differentiation, with its absence leading to near-complete loss of this population in mouse models.^[49] Additional markers support tuft cell identification and highlight their functional attributes. Growth factor independent 1B (GFI1B), a transcriptional repressor, is enriched in tuft cells and regulates their development alongside POU2F3.^[50] Choline acetyltransferase (ChAT), an enzyme for acetylcholine synthesis, marks the secretory subset of tuft cells, particularly those involved in neuromodulation.^[2] Other supporting genes, such as advillin (AVIL) and phospholipase C beta 2 (PLCB2), further define the tuft cell transcriptome and are used in combination for precise delineation.^[51] Identification of tuft cells relies on established techniques that leverage these markers. Immunohistochemistry (IHC) targeting DCLK1 is a standard method for visualizing tuft cells in tissue sections, revealing their characteristic tufted microvilli and basal positioning in the epithelium.^[52] Single-cell RNA sequencing (scRNA-seq) provides a high-resolution approach, clustering tuft cells based on co-expression of DCLK1, TRPM5, POU2F3, and AVIL, often identifying distinct subtypes within the population.^[4] Flow cytometry using surface markers like KIT, which shows over 98% overlap with AVIL-positive tuft cells, enables their isolation from organoids and tissues.^[4] A key challenge in tuft cell identification is their partial overlap with enteroendocrine cells, particularly in markers like Prox1, which labels both lineages and can lead to misclassification in early studies.^[53] This ambiguity is resolved through multi-marker panels combining tuft-specific factors (e.g., POU2F3 and TRPM5) with enteroendocrine hormones (e.g., chromogranin A), ensuring accurate distinction via scRNA-seq or multiplexed IHC.^[54] Recent advances in 2024 have identified markers associated with stem-like states in tuft cells following tissue damage, such as irradiation or inflammation. In human intestinal organoids, surviving tuft cells co-express SOX9 alongside canonical markers like AVIL and POU2F3, enabling their transition to a regenerative progenitor state capable of generating multiple epithelial lineages.^[4] SOX9 knockout reduces tuft cell frequency and impairs this damage response, underscoring its role in post-injury plasticity.^[4] These findings, derived from scRNA-seq of damaged tissues, highlight tuft cells as a reserve stem cell pool distinct from homeostatic LGR5+ progenitors.^[4]

Functions

Sensory and Signaling Roles

Tuft cells function as chemosensory epithelial cells, detecting environmental cues through specialized receptors. They express G protein-coupled receptors (GPCRs) such as the succinate receptor GPR91 (also known as SUCNR1), which binds microbial-derived succinate to initiate sensory responses in the intestinal epithelium.^[55] Additionally, tuft cells utilize bitter taste receptors from the TAS2R family to sense bitter metabolites and potential toxins, enabling rapid detection of luminal threats across various tissues.^[56] These receptors allow tuft cells to monitor metabolite levels and allergen presence without relying on immune-specific pathways. Upon ligand binding, tuft cells activate a taste-like intracellular signaling cascade. Receptor activation recruits heterotrimeric G proteins, leading to the stimulation of phospholipase C β2 (PLCβ2), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 then binds to IP3 receptors on the endoplasmic reticulum, triggering calcium release into the cytosol and subsequent activation of the transient receptor potential channel TRPM5, which further amplifies calcium influx and depolarization.^[56] This pathway, conserved across tuft cell populations, facilitates quick signal transduction for environmental surveillance. Activated tuft cells secrete paracrine mediators to communicate with neighboring cells. They release acetylcholine (ACh), which binds to muscarinic receptors on adjacent epithelial cells or smooth muscle, promoting chloride secretion and fluid dynamics in the gut or modulating contractility in other tissues.^[57] Tuft cells also produce prostaglandins such as PGE2 and PGD2, which act on nearby nerves or smooth muscle to influence local reflexes and inflammation-independent responses.^[58] In non-immune contexts, tuft cells contribute to sensory homeostasis in diverse organs. In the airways, they detect bitter irritants, triggering ACh release to enhance mucociliary clearance without invoking type 2 immunity.^[21] Similarly, in the urethra and bladder, tuft cells sense irritants via bitter tastants, releasing ACh to activate sensory nerves and elicit protective reflexes such as micturition or local neurogenic responses.^[26] Tuft cells also contribute to antibacterial defenses through interactions regulated by RANK signaling (as of August 2025; preprint).^[59] Recent findings from December 2024 indicate that tuft cell sensory functions exhibit circadian rhythms, with higher abundance and expression at dusk—aligning with active feeding phases—to optimize metabolite detection in the gut.^[60] This diurnal variation, regulated by histone deacetylase 3 (HDAC3) and microbial cues, underscores tuft cells' role in timed environmental monitoring.^[61]

Role in Type 2 Immunity

Tuft cells play a pivotal role in initiating type 2 immune responses, particularly in the intestinal epithelium, where they sense luminal signals from helminths such as the metabolite succinate derived from parasite infection.^[62] Succinate binds to the G-protein-coupled receptor SUCNR1, which is selectively expressed on tuft cells, triggering calcium influx and subsequent secretion of interleukin-25 (IL-25).^[62] This IL-25 acts as an alarmin cytokine that activates type 2 innate lymphoid cells (ILC2s) in the lamina propria.^[63] IL-25 binding to its receptor on ILC2s promotes the rapid production and release of interleukin-13 (IL-13), which in turn drives the differentiation and expansion of tuft and goblet cells, leading to epithelial hyperplasia.^[64] This hyperplasia enhances mucus production and intestinal motility, contributing to the expulsion of helminth parasites.^[64] A key feedback mechanism sustains this response: IL-13 signals through the transcription factor STAT6 to amplify tuft cell numbers from epithelial progenitors, thereby reinforcing IL-25 production and the overall type 2 circuit.^[65] However, tuft cells can also restrain intestinal type 2 immunity through the transcription factor Gfi1, preventing excessive responses (as of July 2025).^[13] In allergic contexts, tuft cells in the airways exhibit a analogous mechanism, responding to aeroallergens by secreting IL-25 and cysteinyl leukotrienes, which activate ILC2s and initiate type 2 inflammation characterized by eosinophil recruitment and mucus hypersecretion. This contributes to the pathology of asthma, where tuft cell-derived signals exacerbate airway hyperresponsiveness.^[58] Experimental evidence from mouse models underscores these roles; ablation of tuft cells using Pou2f3-deficient mice, which lack functional tuft cells, results in diminished IL-25 production, impaired ILC2 activation, reduced IL-13 levels, and failure to clear helminth infections such as Tritrichomonas or Nippostrongylus brasiliensis.^[66] Similarly, Trpm5 knockout mice, which disrupt tuft cell chemosensory function, show defective tuft cell expansion and weakened type 2 responses to protozoan parasites.^[64] These studies from 2016 to 2020 highlight tuft cells as essential initiators of the IL-25/IL-13 axis in type 2 immunity.^[63]

Regenerative Functions

Tuft cells have emerged as a critical reserve cell population in epithelial regeneration, particularly in the intestine, where they demonstrate resilience to injury and the capacity to replenish damaged tissue. Unlike conventional Lgr5+ stem cells, which are highly sensitive to genotoxic stress, tuft cells survive severe insults such as irradiation and subsequently dedifferentiate to adopt stem-like properties, enabling them to drive tissue repair.^[4] This plasticity positions tuft cells as a backup mechanism for maintaining epithelial homeostasis when primary stem cell pools are depleted.^[4] A pivotal 2024 study in human intestinal organoids revealed that tuft cells can generate all major epithelial lineages, including enterocytes, goblet cells, and enteroendocrine cells, following damage where Lgr5+ progenitors fail.^[4] Upon irradiation at doses of 5–6 Gy, tuft cells upregulate stem-like genes such as ASCL2, BMI1, and SOX4, though not LGR5 or OLFM4 directly; however, isolated tuft cells express LGR5 after seeding into organoids, underscoring their reprogrammable potential.^[4] This dedifferentiation allows single tuft cells to form fully differentiated organoids, highlighting their role as quiescent progenitors activated post-injury.^[4] The transition to a proliferative state in tuft cells is mediated by interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling, which induces a 10–15-fold increase in tuft cell numbers and promotes expression of growth factors like epiregulin (EREG).^[4] In the intestinal context, this mechanism supports regeneration after infections or inflammatory bowel disease (IBD) flares, where a specific tuft cell subset (tuft-4) contributes to both immune modulation and epithelial renewal.^[4] Evidence for similar regenerative functions in the airways remains limited, with current research primarily focused on intestinal models, though tuft cells' presence in airway epithelium suggests potential parallels warranting further investigation.^[4] Overall, these findings imply that tuft cells serve as a "reserve pool" for epithelial homeostasis, offering therapeutic promise for enhancing recovery in injury-prone tissues like the gut.^[4] By bypassing the vulnerabilities of active stem cells, tuft cells ensure robust tissue integrity under stress, as evidenced by their expression of survival markers such as TACSTD2 and ANXA1.^[4]

Pathophysiological Roles

In Parasitic Infections

Tuft cells play a pivotal role in the host response to intestinal parasitic infections, particularly helminths, by undergoing rapid hyperplasia upon detection of the pathogen. In mouse models of infection with Nippostrongylus brasiliensis, a nematode helminth, tuft cell numbers expand dramatically from a baseline of approximately 1% to over 10% of the epithelial population within days, driven by a feedback loop involving IL-13 signaling that promotes further differentiation from epithelial progenitors.^[64] This hyperplasia facilitates parasite expulsion by amplifying type 2 immune responses, which lead to goblet cell proliferation, increased mucus production, and enhanced intestinal peristalsis through smooth muscle hypercontractility.^[67] Similar tuft cell expansion occurs during infections with other helminths, such as Heligmosomoides polygyrus and Trichinella spiralis, underscoring a conserved mechanism for epithelial remodeling in response to luminal threats.^[64] A key mediator in this process is interleukin-25 (IL-25), secreted primarily by activated tuft cells, which initiates the type 2 immune cascade by stimulating group 2 innate lymphoid cells (ILC2s) to produce IL-13, thereby sustaining tuft cell expansion and driving worm clearance.^[64] Experimental evidence from tuft cell ablation models, such as diphtheria toxin-mediated depletion in Dclk1-DTR mice, demonstrates prolonged infections and higher worm burdens in N. brasiliensis-infected animals, with impaired goblet cell hyperplasia and reduced mucus secretion confirming the essential role of tuft cells in host defense.^[64] In humans, correlations with hookworm (Necator americanus or Ancylostoma duodenale) infections suggest analogous mechanisms, as elevated type 2 cytokines like IL-25 and IL-13 are observed in endemic areas, though direct tuft cell quantification remains limited due to challenges in sampling infected epithelia.^[67] Beyond helminths, tuft cells contribute to defenses against protozoan parasites, such as Giardia muris, by sensing microbial metabolites like succinate through the G protein-coupled receptor SUCNR1, triggering IL-25 release and a type 2 response that promotes parasite clearance via epithelial barrier reinforcement.^[68] Studies in Giardia-infected mice reveal tuft cell activation and modest hyperplasia, often modulated by microbiota dysbiosis that elevates succinate levels, highlighting tuft cells' role in integrating commensal and pathogenic signals during protozoan infections.^[69] A 2024 review positions tuft cells as epithelial "sentinels" that balance efficient parasite expulsion against potential immunopathology, as excessive type 2 responses can lead to tissue damage, emphasizing their context-dependent regulation in infection outcomes.^[70]

In Inflammatory and Autoimmune Diseases

Tuft cells exhibit dysregulation in inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, where their numbers are often reduced in inflamed tissues, correlating with disease severity. However, IL-13-driven type 2 immune responses can induce tuft cell hyperplasia, which promotes goblet cell differentiation and mucus production but may contribute to pathological remodeling when excessive. This hyperplasia correlates with elevated IL-13 levels, exacerbating fibrosis through metabolic-immune crosstalk involving the tuft cell-IL-25 axis. In human IBD patients, reduced tuft cell numbers (e.g., 55% decrease in ulcerative colitis colon tissues) correlate with severity, as observed in biopsy analyses.^[71] Tuft cells express succinate receptor 1 (SUCNR1), which senses elevated succinate levels from dysbiotic microbiota to trigger IL-25 and IL-13 release, promoting type 2 responses that support epithelial repair and suppress inflammation in IBD, though succinate may exacerbate colitis via effects on other immune cells such as Tregs.^[71]^[72] In autoimmune conditions like asthma, airway tuft cells play a potential role through activation in type 2 inflammation. IL-13 programs these tuft cells to produce prostaglandin E2 (PGE2), enhancing mucociliary clearance via CFTR-dependent mechanisms, though chronic activation may perpetuate allergic responses.^[58] Therapeutic strategies targeting tuft cells, such as IL-25 inhibition, show promise in preclinical models from 2023-2025 for reducing inflammation in IBD. Blocking IL-25 ameliorates Th2-driven pathology in ulcerative colitis by suppressing excessive type 2 responses while preserving barrier repair.^[71] A 2025 review highlights tuft cells as double-edged swords in IBD progression, where their protective sensing functions can shift to pro-inflammatory overactivation, driving chronic inflammation and fibrosis without infectious triggers.^[71]

In Cancer and Metabolic Disorders

Tuft cells have been implicated in colorectal cancer (CRC) progression through their secretion of interleukin-25 (IL-25), which recruits type 2 innate lymphoid cells (ILC2s) to foster a tumor-permissive microenvironment. In CRC models, tuft cell-derived IL-25 activates ILC2s, leading to the release of cytokines such as IL-13 and IL-5, which promote epithelial proliferation and suppress anti-tumor immunity, ultimately enhancing tumor growth and metastasis.^[73] Recent analyses confirm elevated tuft cell numbers and IL-25 expression in human CRC tissues, correlating with poorer patient outcomes and highlighting this axis as a key driver in inflammation-associated carcinogenesis.^[74] Beyond direct cytokine effects, tuft cells exhibit stem-like properties that may contribute to cancer stem cell (CSC) pools, particularly following chemotherapy. Marked by doublecortin-like kinase 1 (DCLK1) expression, tuft cells demonstrate resistance to genotoxic damage, such as irradiation, and can dedifferentiate to regenerate epithelial lineages, including in post-treatment settings where they support tumor repopulation. In human intestinal organoids, DCLK1+ tuft cells survive radiation exposure and proliferate under IL-4/IL-13 stimulation to drive repair, suggesting a role in enriching CSC populations after chemotherapeutic depletion of primary tumor cells.^[4] In metabolic disorders, tuft cell activity oscillates with diurnal eating and sleeping cycles, influencing obesity through regulation of gut immunity and hormone signaling. A 2024 study from Carnegie Mellon University revealed that tuft cell biogenesis peaks at dusk—aligning with the onset of the active feeding phase in mice—and is controlled by the histone deacetylase HDAC3, which integrates microbial and TGF-β cues to modulate tuft cell numbers.^[60] Disruptions in tuft cell numbers, as observed in high-fat diet-induced obesity models, alter gut lumen surveillance and may dysregulate enteroendocrine hormone release (e.g., GLP-1), exacerbating metabolic inflammation.^[75] Tuft cells emerge in pancreatic ductal metaplasia during chronic injury, contributing to acinar-to-ductal transdifferentiation.^[76] Therapeutically, targeting tuft cell markers like DCLK1 holds promise for gastrointestinal cancers by depleting CSC reservoirs and disrupting oncogenic signaling. Small-molecule inhibitors such as LRRK2-IN-1 potently suppress DCLK1 kinase activity, reducing proliferation, migration, and invasion in CRC and pancreatic cancer cell lines while enhancing chemotherapy sensitivity. Clinical translation is supported by preclinical data showing DCLK1 ablation attenuates tumor initiation in ApcMin/+ mice, positioning these agents as adjuncts to standard therapies for tuft cell-driven malignancies.^[77]

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Tuft cells are rare, primarily endoderm-derived, epithelial cells present predominantly at mucosal surfaces of vertebrates. Named for the iconic apical cluster ...
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Tuft cells: Context specific programming for a conserved cell lineage
Aug 22, 2023 · Tuft cells are found across tissues that have distinct stem cell compartments, varied tissue architecture, and diverse luminal exposures.
[10]
Intestinal Tuft Cells - Abdominal Key
Apr 21, 2019 · Defining features of a tuft cell include: (1) an apical tuft of microvilli; (2) a relatively narrow apical membrane, which leads to the ...<|separator|>
[11]
https://pubmed.ncbi.nlm.nih.gov/22527717/
[12]
Distinct ATOH1 and Neurog3 requirements define tuft cells as a new ...
Mar 7, 2011 · Results. A set of molecular markers allows unambiguous identification of tuft cells in the mouse intestinal epithelium. Trpm5-expressing cells, ...
[13]
Organization of a cytoskeletal superstructure in the apical domain of ...
Oct 1, 2024 · Tuft cells are a rare epithelial cell type that play important roles in sensing and responding to luminal antigens. A defining morphological ...
[14]
The intestinal tuft cell nanostructure in 3D | Scientific Reports - Nature
May 10, 2017 · We identified and documented the volumetric ultrastructure at nanometer resolution (4–5 nm/pixel) of specific intestinal tuft cells.Introduction · Results And Discussion · Methods
[15]
https://rupress.org/jcb/article/223/12/e202404070/277004/Organization-of-a-cytoskeletal-superstructure-in
[16]
Novel protocol to observe the intestinal tuft cell using transmission ...
Feb 16, 2022 · To date, electron microscopic approaches have shown various morphological features of the tuft cell, such as long and thick microvilli, ...
[17]
https://www.annualreviews.org/doi/full/10.1146/annurev-physiol-042022-030310
[18]
Intestinal Tuft Cells: Morphology, Function, and Implications for ...
Tuft cells are a rare and morphologically distinct chemosensory cell type found throughout many organs, including the gastrointestinal tract.
[19]
Human airway tuft cells influence the mucociliary clearance through ...
Nov 4, 2023 · Absence of cilia and basal bodies with predominance of brush cells in the respiratory mucosa from a patient with immotile cilia syndrome.
[20]
https://pmc.ncbi.nlm.nih.gov/articles/PMC11193883/
[21]
https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-023-02570-8
[22]
Distribution pattern and molecular signature of cholinergic tuft cells ...
Nov 25, 2019 · Tuft cells represent a minor sub-population of post-mitotic epithelial cells in the mucosal lining of the mammalian alimentary tract. On the ...<|control11|><|separator|>
[23]
Bitter triggers acetylcholine release from polymodal urethral ... - PNAS
May 19, 2014 · Urethral brush cells express bitter and umami taste receptors and downstream components of the taste transduction cascade; respond to ...
[24]
https://www.nature.com/articles/s41598-019-53997-3
[25]
Interpreting heterogeneity in intestinal tuft cell structure and function
May 1, 2018 · Intestinal tuft cells are a morphologically unique cell type, best characterized by striking microvilli that form an apical tuft.
[26]
Distribution pattern and molecular signature of cholinergic tuft cells ...
Nov 25, 2019 · While absent from the human stomach, cholinergic tuft cells localized to villi and crypts in the small and large intestines.Missing: gastrointestinal | Show results with:gastrointestinal
[27]
Human airway tuft cells influence the mucociliary clearance through ...
Nov 4, 2023 · Background: Airway tuft cells, formerly called brush cells have long been described only morphologically in human airways. More recent ...
[28]
Tuft cells are key mediators of interkingdom interactions at mucosal ...
Mar 10, 2022 · Despite their rarity, tuft cells have been found in the respiratory tract, gastrointestinal tract, urogenital tract, and thymus at varying ...Missing: genitourinary | Show results with:genitourinary<|separator|>
[29]
A nasal cell atlas reveals heterogeneity of tuft cells and their role in ...
May 25, 2024 · TRPM5+ microvillous cells, which are tuft cells, regulate olfactory stem cell proliferation in the nasal olfactory neuroepithelium.
[30]
Thymic tuft cells: potential “regulators” of non-mucosal tissue ...
Mar 24, 2023 · Thymic tuft cells have been demonstrated to be involved in and play vital roles in immune responses such as antigen presentation, immune tolerance, and type 2 ...
[31]
Doublecortin-like kinase 1-positive enterocyte - a new cell ... - PubMed
Sep 28, 2016 · In murine intestine, DCLK1 marks tuft cells with characteristic microvilli, features of neuroendocrine cells and also quiescent stem cell-like ...<|separator|>
[32]
Tuft cells are key mediators of interkingdom interactions at mucosal ...
Mar 10, 2022 · Although tuft cells were discovered over 60 years ago, their functions have long been enigmatic, especially in human health.Missing: Chlopkov 1920s
[33]
[PDF] Road salt compromises functional morphology of larval gills in ...
New insights into fish ion regulation and mitochondrion-rich cells. ... Cell Area. Area of gill tuft cells as defined by cell borders at apical epithelium.
[34]
Road salt compromises functional morphology of larval gills in ...
Dec 27, 2020 · The increase in cell density on tufts was attributable to changes in cell shape, allowing tighter packing of cells on the gill tufts. An ...
[35]
Cellular landscape of avian intestinal organoids revealed by single ...
Apr 2, 2025 · Identified heterogeneity within the epithelial lineage included enterocytes, goblet cells, Paneth cells, tuft cells, and diverse enteroendocrine ...
[36]
Identification of the Paneth cells in chicken small intestine
Jul 1, 2016 · The Paneth cells are restricted to the crypts of the small intestine, along with goblet cells, enterocytes, tuft cells, and enteroendocrine ...
[37]
Metabolomic and functional analyses of small molecules secreted ...
Intestinal helminth parasites trigger the host immune response through epithelial sensory tuft cells, but helminth-derived molecules that may activate tuft ...
[38]
Tuft Cells Increase Following Ovine Intestinal Parasite Infections and ...
Nov 22, 2021 · We identify and characterize tuft cells in the ovine abomasum (true stomach of ruminants) and show that they increase significantly in number following ...
[39]
Tuft Cells Increase Following Ovine Intestinal Parasite Infections and ...
Nov 21, 2021 · Our findings reveal a tuft cell response to economically important parasite infections and show that while tuft cell effector functions have ...Missing: analogs invertebrates
[40]
Distinct ATOH1 and Neurog3 requirements define tuft cells as a new ...
Mar 7, 2011 · Since their first identification in the rat trachea (Rhodin and Dalhamn, 1956) and mouse gastrointestinal tract (Jarvi and Keyrilainen, 1956) ...All Dclk1 Cells Are Post... · Dclk1 Tuft Cells Are... · Tuft Cells Represent A...
[41]
https://moredun.org.uk/research/scientific-papers/metabolomic-and-functional-analyses-of-small-molecules-secreted-by-intestinal-nematodes-in-the-activation-of-epithelial-tuft-cells
[42]
Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft ...
Sep 3, 2022 · In turn IL4/IL13 signals to the stem cells within the intestinal crypt and promotes tuft and goblet cell hyperplasia. STAT6 is a ...
[43]
Tuft cell‐derived IL‐25 activates and maintains ILC2 - Gronke - 2016
Mar 1, 2016 · It is remarkable that tuft cells are found in the intestine only 1–2 weeks after birth, at a time when profound changes in nutrient and ...Missing: timeline | Show results with:timeline
[44]
Dclk1-expressing tuft cells: critical modulators of the intestinal niche?
... role of tuft cells within the intestinal niche. Tuft Cells ... Pulmonary neuroendocrine cells function as airway sensors to control lung immune response.
[45]
The critical roles and therapeutic implications of tuft cells in cancer
Dec 8, 2022 · Tuft cells are unusual epithelial cells that were firstly observed in an apical brush border of the rat trachea by Rhodin et al. 60 years ago ( ...Abstract · Introduction · Discussion
[46]
Generation and functional characterization of tuft cells in non-human ...
May 6, 2025 · In this study, we report the generation of pancreatic ductal organoids from non-human primates for the first time, aimed at investigating the role of tuft ...
[47]
[PDF] Mature tuft cell phenotypes are sequentially expressed along the ...
Nov 29, 2024 · Unsupervised clustering revealed three clusters (Fig. 1a), each with clear expression of general tuft cell markers such as Dclk1, Trpm5, Avil, ...
[48]
Tuft Cells and Their Role in Intestinal Diseases - Frontiers
Tuft cells have proven indispensable in anti-helminthic and anti-protozoan immunity. Most studies on tuft cells are based on murine experiments using double ...Missing: Chlopkov 1920s
[49]
Intestinal enteroendocrine lineage cells possess homeostatic ... - NIH
The study found that enteroendocrine lineage cells, specifically Bmi1-GFP+ and Prox1+ cells, possess intestinal stem cell activity during homeostasis and ...
[50]
Single-cell sequencing of rotavirus-infected intestinal epithelium ...
Nov 3, 2021 · The lack of RV transcripts in EECs could also be due to previous studies cross-detecting EECs and tuft cells; some reports indicate overlap in ...
[51]
Detection of Succinate by Intestinal Tuft Cells Triggers a ... - PubMed
Jul 17, 2018 · Here, we identified the microbial metabolite succinate as an activating ligand for small intestinal (SI) tuft cells. Sequencing analyses of tuft ...Missing: TAS2R | Show results with:TAS2R
[52]
Infection by the parasitic helminth Trichinella spiralis activates a ...
Feb 28, 2019 · T. spiralis Infection Triggers Tuft- and Goblet-Cell Hyperplasia in the Mouse Duodenum, Jejunum, and Ileum. Since different parasitic helminths ...
[53]
IL-13–programmed airway tuft cells produce PGE 2 ... - JCI Insight
May 24, 2022 · We found that IL-13 expanded and programmed airway tuft cells toward eicosanoid metabolism and that tuft cell deficiency led to a reduction in airway ...Missing: STAT6 seminal
[54]
HDAC3 integrates TGF-β and microbial cues to program tuft cell ...
Sep 27, 2024 · We show that histone deacetylase 3 (HDAC3) controls tuft cell specification and the diurnal rhythm of its biogenesis, which is regulated by the gut microbiota ...
[55]
Tuft Cell Expression Changes with Sleeping, Eating Cycles
Dec 12, 2024 · We found abundance of the sentinel tuft cells is higher at dusk, the beginning of the active phase, and low at dawn, the beginning of the resting phase.Missing: circadian | Show results with:circadian
[56]
Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 ...
May 7, 2018 · Abstract. The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation.
[57]
Tuft-cell-derived IL-25 regulates an intestinal ILC2 ... - Nature
Dec 14, 2015 · Here we show that tuft cells constitutively express IL-25 to sustain ILC2 homeostasis in the resting lamina propria in mice.
[58]
Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 ...
Our results identify intestinal tuft cells as critical sentinels in the gut epithelium that promote type 2 immunity in response to intestinal parasites.Tuft Cells... · Tuft Cells Help Contain... · Abstract
[59]
Selective expression of constitutively activated STAT6 in intestinal ...
Nov 16, 2018 · Our results reveal an important IEC-intrinsic role of STAT6-regulated genes for intestinal homeostasis and protective immunity against helminths.
[60]
Intestinal tuft cells: epithelial sentinels linking luminal cues to the ...
Aug 24, 2016 · Here we review tuft cell functions and markers, and anchors epithelial tuft cells within the current paradigm of type 2 immune responses.The Tuft Cell Type: From A... · Tuft Cells Initiate Type 2... · Trpm5 And Taste Receptor...
[61]
Tuft Cells: Detectors, Amplifiers, Effectors and Targets in Parasite ...
Oct 18, 2023 · Tuft cells have recently emerged as the focus of intense interest following the discovery of their chemosensory role in the intestinal tract.
[62]
Enteric Tuft Cells in Host-Parasite Interactions - MDPI
Tuft cells, commonly referred to in early studies as brush cells, are aptly named for their characteristic tuft-shaped apical microvilli [12,13]. They ...
[63]
The Interplay Between Enteric Tuft Cell Responses and Giardia ...
May 13, 2022 · Using Giardia murisas a model, this study aims to uncover novel roles for tuft cells in the pathophysiology of giardiasis by assessing the tuft ...
[64]
Tuft cell acetylcholine is released into the gut lumen to promote anti ...
May 13, 2024 · Tuft cells are a cellular subset mostly found in digestive and respiratory epithelia and play critical roles in mucosal host defense. In the ...
[65]
The role of the tuft cell–interleukin-25 axis in the pathogenesis of ...
Sep 17, 2025 · Similarly, exogenous succinate activates succinate receptor 1 (SUCNR1) on tuft cells, inducing downstream cells to secrete IL-25 and IL-13, ...
[66]
An innate IL-25-ILC2-MDSC axis creates a cancer-permissive ... - NIH
Colorectal cancer (CRC) patients with higher tumor IL25 expression had reduced survival, and increased IL-25R-expressing tumor-resident ILC2s and myeloid- ...Missing: 2024 | Show results with:2024
[67]
https://pmc.ncbi.nlm.nih.gov/articles/PMC10605326/