Distribution pattern and molecular signature of cholinergic tuft cells in human gastro-intestinal and pancreatic-biliary tract

Abstract

Despite considerable recent insight into the molecular phenotypes and type 2 innate immune functions of tuft cells in rodents, there is sparse knowledge about the region-specific presence and molecular phenotypes of tuft cells in the human digestive tract. Here, we traced cholinergic tuft cells throughout the human alimentary tract with immunohistochemistry and deciphered their region-specific distribution and biomolecule coexistence patterns. While absent from the human stomach, cholinergic tuft cells localized to villi and crypts in the small and large intestines. In the biliary tract, they were present in the epithelium of extra-hepatic peribiliary glands, but not observed in the epithelia of the gall bladder and the common duct of the biliary tract. In the pancreas, solitary cholinergic tuft cells were frequently observed in the epithelia of small and medium-size intra- and inter-lobular ducts, while they were absent from acinar cells and from the main pancreatic duct. Double immunofluorescence revealed co-expression of choline acetyltransferase with structural (cytokeratin 18, villin, advillin) tuft cell markers and eicosanoid signaling (cyclooxygenase 1, hematopoietic prostaglandin D synthase, 5-lipoxygenase activating protein) biomolecules. Our results indicate that region-specific cholinergic signaling of tuft cells plays a role in mucosal immunity in health and disease, especially in infection and cancer.

Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling

“…To evaluate Hpgds protein expression, we conducted multiplex immunofluorescence for Hpgds and tuft cell marker phospho-EGFR on metaplasia and PanINbearing human pancreatitis samples (5). Though rare, we found that 100% of pancreatitis tuft cells (30/30; n=3 patients) express Hpgds at the protein level ( Figure 6C), consistent with studies in normal human pancreas (19). We then conducted eicosanoid profiling on PDA (n=6) and nearby normal pancreas (n=3) ( Figure S14A, File S5), but were unable to include human PanIN due to lack of available fresh tissue.…”

“…These studies suggest that tuft cells play multifaceted roles in sensing and responding to diverse infectious and inflammatory conditions. While tuft cells have been reported in rat and human pancreas, they are not normally present in the murine pancreas (5,19). Rather, we and others showed that tuft cells transdifferentiate from the acinar cell epithelium as part of ADM in response to oncogenic Kras expression (5,20).…”

Acetylcholine From Tuft Cells: The Updated Insights Beyond Its Immune and Chemosensory Functions

“…The discrepancy also occurs in the biliary tract. ChAT + cholinergic tuft cells have been found in extra-hepatic peribiliary glands but are absent in gall bladder and common bile duct epithelium in human ( Schütz et al, 2019 ), whereas they scatter throughout the gall bladder and extra-hepatic bile duct in rodents ( Schütz et al, 2015 ). It’s not confusing that tuft cells should not be defined into one single lineage because of the multiple characteristics and wide dispersal throughout mucosal surfaces.…”

“…Recently, Schütz et al (2019) identified the distribution and molecular signatures of cholinergic tuft cells in human digestive tract, including gastrointestinal, biliary and pancreatic systems. Given that tuft cell is the only epithelial cellular source of ACh in human digestive tract ( Schütz et al, 2019 ), tuft cell-derived cholinergic signaling may play a considerable role and should be paid more attention. In the light of this rationale, this review, summarizing older reviews and novel advances, focuses on the pathophysiological roles of tuft cell derived ACh.…”

Tuft cells: an emerging therapeutic target for pancreatitis and pancreatic cancer?

“…Moreover, several studies have shown that TCs also release acetylcholine to signal to surrounding cell types. These cholinergic TCs are selectively distributed in interlobular ducts in the middle of the pancreas and may play an important role in the immune processes of infection and cancer [10].…”