Interpreting heterogeneity in intestinal tuft cell structure and function

Abstract

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.

RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, uncovering novel vitamin A-regulated genes

“…Tuft cells (also known as brush or caveolated cells) have distinctive apical bristles that form a highly organized brush border, giving the cells their eponymous tufted morphology. Tuft cells represent about 0.5% of the epithelial cells in the murine small and large intestines, with a slightly more prevalent distribution in the distal SI (120). Although the existence of Tuft cell has been known in multiple organs for close to a century, not until recently were they distinguished from enteroendocrine, Paneth, and goblets cells, and raising from three to four the number of secretory cell types in the SI epithelium (121).…”

“…Trpm5 is a well-known Tuft cell marker, encoding a chemosensory protein that regulates ion transport (120). Lastly, another Tuft marker Ptpn6 (122) is a top 5% hub gene of the SI(Yellow) module ( Table 5 and Pou2f3 (Pou domain class 2) is a Tuft-specific TF (122), which encodes a chemosensory protein and functions in wound healing as well as epithelial cell differentiation.…”

“…In the VA deficiency state, the proliferation and function of the ILC3 subset are suppressed and there are marked increases of ILC2 cell proliferation and type 2 cytokine production (9). IL-13 is one of those cytokines that can stimulate the differentiation of epithelial precursor cells towards Tuft cells (120).…”

“…Tuft cells were originally believed to be a type of damage-activated quiescent stem cell, with the expression of the DCLK1 marker and occupation of the +4 position within the intestinal crypt. Since then, new evidence has emerged that Tuft cells may be a major source of prostaglandin E2, which is an inducer of stem cell proliferation to promote post-irradiation tissue recovery (120). Thereby, the chronic mucosal damage in VAD mice might also elevate the Tuft cell population.…”

“…Dclk1 (doublecortin-like kinase 1) is probably the most frequently used Tuft cell marker. Dclk1 participates in the functions of quiescent stem cell and damage recovery(120).…”