The intestinal tuft cell nanostructure in 3D

Hoover, Ben; Baena, Valentina; Kaelberer, Melanie M.; Getaneh, Feven; Chinchilla, Skarleth; Bohórquez, Diego V.

doi:10.1038/s41598-017-01520-x

Cited by 46 publications

(62 citation statements)

References 32 publications

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“…be gathered about peri-nuclear and basal structures. Recently, Hoover et al, used a combination of SBFEM and SEM imaging of serial ultra-thin sections to describe ultrastructural features of intestinal tuft in 3D (32). Therefore, to more completely evaluate pancreatic tuft cell ultrastructure, we performed SBFEM on PanIN from 6 and 12 month old KC mice.…”

Section: Identification Of Tuft Cells By Apical Microvilli Captured Imentioning

confidence: 99%

Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling

DelGiorno

Chung

et al. 2019

Preprint

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Despite numerous advances in our understanding of pancreatic ductal adenocarcinoma (PDA) genetics and biology, this disease is expected to become the second leading cause of cancer-related U.S. deaths within the next few years. Incomplete understanding of how it arises precludes development of early detection and interception strategies to improve therapeutic outcomes. Acinar to ductal metaplasia involving genesis of tuft cells is one early step in PDA formation, but their functional significance has remained obscure due to their rarity and a lack of methods and relevant animal models for their molecular and functional analysis. Here, we show that deletion of tuft cell master regulator Pou2f3 eliminates pancreatic tuft cells and increases fibrosis, alters immune cell activation, and accelerates disease progression. We demonstrate that tuft cell expression of the prostaglandin D 2 synthase Hpgds restrains pancreatic disease progression in early stages by inhibiting stromal activation. Analyses of human data sets are consistent with mouse studies. We propose that tuft cells and, by inference, the associated metaplastic lesions, play a protective role early in pancreatic tumorigenesis. Significance:We find that tuft cell formation in response to oncogenic Kras is protective and restrains tumorigenesis through local production of anti-inflammatory substances, including paracrine prostaglandin D 2 signaling to the stroma. Our findings establish tuft cells as a metaplasia-induced tumor suppressive cell type. Introduction:Chemical or mechanical injury of the pancreas results in a cell state-switching event termed acinar to ductal metaplasia (ADM) where digestive enzyme producing acinar cells dedifferentiate into proliferative ductal-like cells to restore pancreas homeostasis. This process is perturbed during neoplastic progression, where, in mouse models, initiating Kras mutations prevent tissue healing and, instead, ADM is thought to progress to pancreatic intraepithelial neoplasia (PanIN) and then pancreatic ductal adenocarcinoma (PDA). This is an example of Dvorak's thesis, which states that cancer represents the ever-healing wound (1).The profound difference between the normal healing process and the perturbed response engendered by oncogene activation raises the important question of whether key cell types that result from ADM impact cancer progression. Here, we investigate the role of tuft cells as they appear in response to oncogeneinduced metaplasia in a number of cancers of human significance including lung, stomach, intestine, and pancreas (2-6).Tuft cells are solitary chemosensory cells found throughout the hollow organs of the respiratory and digestive tracts. They are readily identified by their striking morphological features, including long, blunt microvilli, deep actin rootlets, and an extensive tubulovesicular system in the supranuclear cytoplasm (7).Their expression of taste, neuronal, and inflammatory cell signaling factors is thought to enable monitoring of intraluminal homeostasis and to achieve loc...

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Section: Identification Of Tuft Cells By Apical Microvilli Captured Imentioning

confidence: 99%

Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling

DelGiorno

Chung

et al. 2019

Preprint

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“…Early studies describing tuft cells in rodent models noted the distinctive apical bristles that formed a highly organized brush border, giving these cells their eponymous tufted morphology (1,2,11,28,34). The distribution and dimensions of tuft cell microvilli, summarized in Table 1, are profoundly different from those of neighboring enterocytes (35,36). Unlike enterocytes, tuft cells do not possess a terminal web at the base of apical microvilli and possess a thinner fucose-rich glycocalyx above their apical membrane (15,21,28).…”

Section: Tuft Cell Morphologymentioning

confidence: 99%

“…However, limitations of conventional transmission electron microscopy could not provide the resolution necessary to characterize these protrusions, recently termed "cytospinules" by Hoover et al (Figure 1 and ref. 36). Each tuft cell possesses 3-4 such projections, and a cytospinule can pierce the lateral membrane of a neighboring cell, making direct contact with its nuclear membrane (36).…”

Section: Tuft Cell Morphologymentioning

confidence: 99%

“…36). Each tuft cell possesses 3-4 such projections, and a cytospinule can pierce the lateral membrane of a neighboring cell, making direct contact with its nuclear membrane (36). While the point of connection appears electron dense and its exact purpose remains unclear, it may be postulated that this tuft cell-to-neighboring cell contact serves as a direct means of communication or cargo transport.…”

Section: Tuft Cell Morphologymentioning

confidence: 99%

“…spheres containing indeterminate cargo (21,39,40). More recent studies using volumetric electron microscopy offered increased resolution into the cytoplasmic contents of intestinal tuft cells (36,43). Using a ChAT:GFP::Pyy-Cre:TdTomato transgenic mouse, Hoover et al identified choline acetyltransferase + (ChAT + ) tuft cells in the intestine (44) that were distinguishable from peptide YY-secreting (PYY-secreting) enteroendocrine cells (36,43).…”

Section: Tuft Cell Morphologymentioning

confidence: 99%

See 2 more Smart Citations

Interpreting heterogeneity in intestinal tuft cell structure and function

Banerjee¹,

McKinley²,

Moltke³

et al. 2018

Journal of Clinical Investigation

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Intestinal tuft cells are a morphologically unique cell type, best characterized by striking microvilli that form an apical tuft. These cells represent approximately 0.5% of gut epithelial cells depending on location. While they are known to express chemosensory receptors, their function has remained unclear. Recently, numerous groups have revealed startling insights into intestinal tuft cell biology. Here, we review the latest developments in understanding this peculiar cell type's structure and function. Recent advances in volumetric microscopy have begun to elucidate tuft cell ultrastructure with respect to its cellular neighbors. Moreover, single-cell approaches have revealed greater diversity in the tuft cell population than previously appreciated and uncovered novel markers to characterize this heterogeneity. Finally, advanced model systems have revealed tuft cells' roles in mucosal healing and orchestrating type 2 immunity against eukaryotic infection. While much remains unknown about intestinal tuft cells, these critical advances have illuminated the physiological importance of these previously understudied cells and provided experimentally tractable tools to interrogate this rare cell population. Tuft cells act as luminal sensors, linking the luminal microbiome to the host immune system, which may make them a potent clinical target for modulating host response to a variety of acute or chronic immune-driven conditions.

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Tuft cell integration of luminal states and interaction modules in tissues

Schneider

2021

Pflugers Arch - Eur J Physiol

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Chemosensory processes are integral to the physiology of most organisms. This function is typically performed by specialized cells that are able to detect input signals and to convert them to an output dedicated to a particular group of target cells. Tuft cells are cholinergic chemosensory epithelial cells capable of producing immunologically relevant effector molecules. They are scattered throughout endoderm-derived hollow organs and function as sensors of luminal stimuli, which has been best studied in mucosal barrier epithelia. Given their epithelial origin and broad distribution, and based on their interplay with immune pathways, tuft cells can be considered a prototypical example of how complex multicellular organisms engage innate immune mechanisms to modulate and optimize organ physiology. In this review, I provide a concise overview of tuft cells and discuss how these cells influence organ adaptation to dynamic luminal conditions.

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The intestinal tuft cell nanostructure in 3D

Cited by 46 publications

References 32 publications

Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling

Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling

Interpreting heterogeneity in intestinal tuft cell structure and function

Tuft cell integration of luminal states and interaction modules in tissues

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