Adhesion receptor ADGRG2/GPR64 is in the GI-tract selectively expressed in mature intestinal tuft cells

Grunddal, Kaare V.; Tonack, Sarah; Egerod, Kristoffer L.; Thompson, Jonatan J; Petersen, Natalia; Engelstoft, Maja S.; Vagne, Constance; Keime, Céline; Gradwohl, Gérard; Offermanns, Stefan; Schwartz, Thue W.

doi:10.1016/j.molmet.2021.101231

Cited by 15 publications

(20 citation statements)

References 82 publications

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“…IHC staining for POU2F3 demonstrates a lack of expression in KPouC pancreata ( Figure 7C ). Additionally, COX1, a marker of mature tuft cells, is absent from the epithelium of KPouC pancreata, consistent with a lack of tuft cell formation ( Figure 7D ) ( Grunddal et al, 2021 ; Ma et al, 2021 ; Manco et al, 2021 ). Interestingly, SYP+ cells were identified in both KC and KPouC pancreata indicating that EEC formation is not prevented by the loss of POU2F3 ( Figure 7D ).…”

Section: Resultssupporting

confidence: 58%

Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of only 11%, due, in part, to late diagnosis, making the need to understand early events in tumorigenesis critical. Acinar-to-ductal metaplasia (ADM), when not resolved, is a PDAC precursor. Recently, we showed that ADM is constituted by a heterogenous population of cells, including hormone-producing enteroendocrine cells (EECs: gamma, delta, epsilon, and enterochromaffin cells). In this study, we employed histopathological techniques to identify and quantify the abundance of EEC subtypes throughout pancreatic tumorigenesis in mouse models and human disease. We found that EECs are most abundant in ADM and significantly decrease with lesion progression. Co-immunofluorescence identifies distinct lineages and bihormonal populations. Evaluation of EEC abundance in mice lacking Pou2f3 demonstrates that the tuft cell master regulator transcription factor is not required for EEC formation. We compared these data to human neoplasia and PDAC and observed similar trends. Lastly, we confirm that EECs are a normal cellular compartment within the murine and human pancreatic ductal trees. Altogether, these data identify EECs as a cellular compartment of the normal pancreas, which expands early in tumorigenesis and is largely lost with disease progression.

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Section: Resultssupporting

confidence: 58%

Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis

et al. 2022

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“…They are usually distributed in a sporadic and solitary manner, accounting for just 0.4-2.3% of the total epithelial cell population in murine intestinal epithelium (9,(20)(21)(22), while the only study on TC density of the human sigmoid colon report ~100 TCs per square millimeter tissue (23). Upon leaving the crypts, migrating along the villus axis, the function of TCs might change with increasing differentiation similar to what has recently been described for enteroendocrine cells (24)(25)(26). While the average TC has a turnover rate of 1-2 weeks (27), a small subpopulation of cells (~5%) expressing double cortin-like kinase 1 (DCLK1), a TC marker in mice, is remarkably longlived, surviving for up to 18 months.…”

Section: Intestinal Tcs and Originmentioning

confidence: 76%

“…Receptor tyrosine kinases have also been identified in TCs, although the mechanism of activation is unclear. Basolateral signaling include other receptors, although not fully elucidated, such as gamma aminobutyric acid (GABA)-receptors in small intestinal TCs ( 55 , 56 ), dopamine receptor Drd3 ( 22 , 55 ), and the orphan adhesion G protein receptor ADGRG2 ( 26 ). Lastly, a recent study report a pathway for IgG activation of intestinal TCs, although only in a minor subpopulation of about 2.75% of TCs in the mouse small intestine ( 57 ).…”

Section: Intestinal Tcs and Originmentioning

confidence: 99%

Tuft Cells and Their Role in Intestinal Diseases

et al. 2022

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The interests in intestinal epithelial tuft cells, their basic physiology, involvement in immune responses and relevance for gut diseases, have increased dramatically over the last fifteen years. A key discovery in 2016 of their close connection to helminthic and protozoan infection has further spurred the exploration of these rare chemosensory epithelial cells. Although very sparse in number, tuft cells are now known as important sentinels in the gastrointestinal tract as they monitor intestinal content using succinate as well as sweet and bitter taste receptors. Upon stimulation, tuft cells secrete a broad palette of effector molecules, including interleukin-25, prostaglandin E2 and D2, cysteinyl leukotriene C4, acetylcholine, thymic stromal lymphopoietin, and β-endorphins, some of which with immunomodulatory functions. Tuft cells have proven indispensable in anti-helminthic and anti-protozoan immunity. Most studies on tuft cells are based on murine experiments using double cortin-like kinase 1 (DCLK1) as a marker, while human intestinal tuft cells can be identified by their expression of the cyclooxygenase-1 enzyme. So far, only few studies have examined tuft cells in humans and their relation to gut disease. Here, we present an updated view on intestinal epithelial tuft cells, their physiology, immunological hub function, and their involvement in human disease. We close with a discussion on how tuft cells may have potential therapeutic value in a clinical context.

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“…They express multiple elements of chemosensory machinery including (i) taste receptors (TAS2Rs and TAS1R3), (ii) components of the taste transduction pathway (G-protein associated subunit α-gustducin and TRPM5), and (iii) metabolite sensing receptors [8,21,23,58]. Additionally, ETCs express receptors for endogenous mediators such as IL-25, GABA and dopamine [22,100,107]. To fully comprehend tuft cell involvement in anti-parasitic responses, it is important to investigate the parasite-derived factors that activate ETC responses: an area of study also currently hampered by the lack of specific markers that indicate ETC activation.…”

Section: Tuft Cell-parasite Communication: Which Parasitic Factor Induces the Tuft Cell Response?mentioning

confidence: 99%

Enteric Tuft Cells in Host-Parasite Interactions

Rajeev

Sosnowski

et al. 2021

Pathogens

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Enteric tuft cells are chemosensory epithelial cells gaining attention in the field of host-parasite interactions. Expressing a repertoire of chemosensing receptors and mediators, these cells have the potential to detect lumen-dwelling helminth and protozoan parasites and coordinate epithelial, immune, and neuronal cell defenses against them. This review highlights the versatility of enteric tuft cells and sub-types thereof, showcasing nuances of tuft cell responses to different parasites, with a focus on helminths reflecting the current state of the field. The role of enteric tuft cells in irritable bowel syndrome, inflammatory bowel disease and intestinal viral infection is assessed in the context of concomitant infection with parasites. Finally, the review presents pertinent questions germane to understanding the enteric tuft cell and its role in enteric parasitic infections. There is much to be done to fully elucidate the response of this intriguing cell type to parasitic-infection and there is negligible data on the biology of the human enteric tuft cell—a glaring gap in knowledge that must be filled.

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Adhesion receptor ADGRG2/GPR64 is in the GI-tract selectively expressed in mature intestinal tuft cells

Cited by 15 publications

References 82 publications

Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis

Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis

Tuft Cells and Their Role in Intestinal Diseases

Enteric Tuft Cells in Host-Parasite Interactions

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