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Review
. 2017 Oct 1;313(4):G285-G299.
doi: 10.1152/ajpgi.00073.2017. Epub 2017 Jul 6.

Dclk1-expressing tuft cells: critical modulators of the intestinal niche?

Moritz Middelhoff  1   2 , C Benedikt Westphalen  3 , Yoku Hayakawa  4 , Kelley S Yan  1   5 , Michael D Gershon  6 , Timothy C Wang  1 , Michael Quante  7
Affiliations
Review

Dclk1-expressing tuft cells: critical modulators of the intestinal niche?

Moritz Middelhoff et al. Am J Physiol Gastrointest Liver Physiol. .

Abstract

Dclk1-expressing tuft cells constitute a unique intestinal epithelial lineage that is distinct from enterocytes, Paneth cells, goblet cells, and enteroendocrine cells. Tuft cells express taste-related receptors and distinct transcription factors and interact closely with the enteric nervous system, suggesting a chemosensory cell lineage. In addition, recent work has shown that tuft cells interact closely with cells of the immune system, with a critical role in the cellular regulatory network governing responses to luminal parasites. Importantly, ablation of tuft cells severely impairs epithelial proliferation and tissue regeneration after injury, implicating tuft cells in the modulation of epithelial stem/progenitor function. Finally, tuft cells expand during chronic inflammation and in preneoplastic tissues, suggesting a possible early role in inflammation-associated tumorigenesis. Hence, we outline and discuss emerging evidence that strongly supports tuft cells as key regulatory cells in the complex network of the intestinal microenvironment.

Keywords: cancer initiation; inflammation; intestinal stem cells; niche cell; tuft cell.

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Figures

Fig. 1.
Fig. 1.
The ultrastructure of tuft cells and close interactions with neighboring neurons. A–D: electron-microscopic pictures of tuft cells and neighboring nerve terminals. The tissue was fixed with glutaraldehyde-formaldehyde and further processed specifically for immunoelectron microscopy. A: complete tuft cell body (dashed line) with adjacent, basolateral nerve terminal; bar graph = 5 µm. B: inset of A, vesicles in the tuft cell appear to be directed to and fuse with its basolateral membrane, which is opposed toward a characteristic autonomic nerve terminal; bar graph = 0.5 µm. C: tuft cell apex with tubule vesicles, microvilli, and elegant tight junctions; bar graph = 0.5 µm. D: tuft cell base of the same tuft cell as shown in C, demonstrating close proximity to a nerve terminal with formation of a junction containing typical synaptic cleft material and a vesicle in close proximity; bar graph = 0.5 µm. E: tuft cell labeled by ZSgreen in a Dclk1-DTR-ZSgreen reporter mouse; DCLK1 protein localization usually appears in the cytoplasmic area close to the apex of a tuft cell; bar graph = 25 µm. F: intestinal villus of an induced Wnt1-Cre; Rosa-TomatoRed mouse, which labels neural crest-derived cells and thus enteric neurons; demonstrating a close contact between epithelial tuft cell (stained with anti-DCLK1; green) and the stromal Wnt1 lineage (red); bar graph = 25 µm.
Fig. 2.
Fig. 2.
Tuft cell distribution and location within the gastrointestinal tract. Immunohistochemical staining for doublecortin-like kinase 1 protein (DCLK1; antibody 31704; Abcam) in the stomach and small and large intestine. Interestingly, the squamocolumnar junction between stomach and esophagus bears abundant tuft cells (A), which are less abundant in the corpus of the stomach mucosa (B). C: characteristically, tuft cells are found near +4 position in the crypts of small intestine as well as scattered along the crypt-villus axis. D: similarly, a scattered distribution of tuft cells can be found along colonic crypt epithelium. Bars at left are lower magnifications (×20) = 25 µm, and bars at right and insets are at higher magnifications (×40) = 12.5 µm.
Fig. 3.
Fig. 3.
Tuft cell conduct during chronic inflammation, hyperplasia, and metaplasia and early neoplasia. A: the persisting stimulation by different substrates [high-fat diet (HFD)] or inflammatory stimuli creates a chronic inflammatory microenvironment, which is sensed by tuft cells and potentially stimulates these to signal to either stromal immune cells (IL-25), or modulates the stroma or the stem or progenitor cell compartment [prostaglandins E2 (PGE2), Ach?]. B: persisting inflammation, however, reportedly increases tuft cell count, thus further enhancing tuft cell signaling to adjacent stromal cells (immune cells, eventually also neurons) and stem and progenitor cells. In addition, this environment may also cause an increasing burden of mutations in susceptible cells. C: interestingly, during progression to early neoplasia, tuft cell count has been shown to decrease and even to be absent of more advanced neoplastic tissue. In this scenario, highly proliferative tumor cells appear to take over and orchestrate aberrant proliferation by directing immune cell invasion, neuronal invasion, or neoangiogenesis. Eventually, Dclk1-expressing tuft cells may also undergo epithelial-to-mesenchymal transition (EMT), thereby loosing Dclk1 expression but maintaining tumor growth as actual tumor stem cells.
Fig. 4.
Fig. 4.
Tuft cells are key regulatory intestinal niche cells orchestrating both sensing and signaling. In the enlargements, we outline the 4 major roles of tuft cells within the epithelium elucidated to date: A: α-gustducin and transient receptor potential melastatin subtype 6 (TRPM6) receptors have been shown to enable tuft cells to sense bitter substance. This reportedly causes tuft cell activation (i.e., intracellular Ca2+ influx), with the further transmission of this signal remaining obscure, but eventually being forwarded to a neighboring epithelial cell via recently described cytospinules or afferent ( = aff.) nerve terminal. Also, additional stimuli (such as hypoxia) might activate similar sensing in tuft cells. B: locally, tuft cell survival depends on neuronal stimuli as well as epithelial proliferation depends on the presence of tuft cells to integrate this signal. This might be reflected by their expression of choline acetyltransferase (ChAT), which catalyzes the production of acetylcholine (Ach), which might then signal in a paracrine fashion to promote proliferation in the epithelial stem (SC) or progenitor cell compartment. C: additionally, upon luminal helminth infection sensed via α-gustducin and TRPM5 receptors, tuft cells release IL-25 to actively modulate innate lymphoid cells type 2 (ILC2), which in turn promote goblet and tuft cell expansion by IL-13/IL-4Ra signaling on epithelial stem or progenitor cells. D: ultimately, tuft cells appear to be essential for regeneration during acute tissue injury. This might involve their use of local paracrine signaling (such as Ach and PGE2) to create a noncrypt-base stem cell environment or to modulate the proregenerative Hippo pathway in ISC populations.
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