Dynamic Expansion of Gastric Mucosal Doublecortin-Like Kinase 1–Expressing Cells in Response to Parietal Cell Loss Is Regulated by Gastrin

Doublecortin-like kinase 1 (Dclk1) is considered a reliable marker for tuft cells in the gastrointestinal tract. We investigated the dynamic changes of tuft cells associated with mouse models of oxyntic atrophy and metaplasia in the stomach. Increases in the numbers of Dclk1-positive tuft cells were observed in several models of parietal cell loss. However, the expanded population of Dclk1-expressing cells showed a morphologically distinct structure in apical microvilli and acetylated microtubules, which was not seen in the tuft cells present in the normal gastric mucosa. These microvillar sensory cells (MVSCs) showed no evidence of proliferation. The expansion of the MVSCs induced by oxyntic atrophy was reversible after the return of parietal cells. More important, expansion of MVSCs after induced parietal cell loss was not observed in Gast^–/– mice. Although the Dclk1-expressing cells in the normal gastric mucosa were in part derived from Lrig1-expressing stem cells, the Lrig1-lineaged cells did not produce the expanded Dclk1-expressing cells associated with oxyntic atrophy. These studies indicate that loss of parietal cells leads to the reversible emergence of a novel Dclk1-expressing sensory cell population in the gastric mucosa.Tuft cells, also known as brush or caveolated cells, represent an unusual type of epithelial cell present in multiple organs of the digestive system, including the stomach and the intestine.^1–3 Tuft cells are rare in the epithelial cell layer and are characterized by the presence of a luminally directed tuft, which displays a distinct membrane-covered array of microtubules. The presence of the apical tuft apparatus suggests that tuft cells have functions for detection and transmission of environmental signals.⁴ Tuft cells represent a class of solitary chemosensory cells, because they express several chemoreceptor molecules, such as the guanine nucleotide binding protein α-transducing 3 and the G-protein–coupled taste receptor type 1 member 3.⁵ Although tuft cells are continuously renewed in the epithelial cell layer, mitotic tuft cells have not been observed. These findings suggest that tuft cells are post-mitotic and might originate from other sources. In the intestine, a recent report has suggested that tuft cells may differentiate from Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-positive progenitor cells.⁶ However, no Lgr5-positive stem cells are present in the body of the stomach, so the identity of cells that can produce or differentiate into tuft cells in the stomach fundus is unclear.Recent studies have reported that doublecortin-like kinase (Dclk1)–expressing cells are present in populations of migrating and post-mitotic neurons and in radial glia cells, known as precursors of neural stem cells.⁷ Dclk1-expressing cells are also proposed as stem/progenitor cells in the organs of the gastrointestinal tract,⁸ and Dclk1 is also present in gastric tuft cells.^1,3 We and several other groups have found that Dclk1-expressing cells are a rare cell lineage in the mouse stomach,^1,9 and the gastric Dclk1-expressing cells appear to represent tuft cells, rather than a stem/progenitor cell population.¹ We have also reported that Dclk1-expressing tuft cells are found in association with invasive neoplastic lesions from the forestomach or glandular transition zone in the Smad3-null mouse stomachs.⁹ Although the Dclk1-expressing cells were highly expanded during gastric tumor progression in the fundic glands of Smad3-null mouse stomach, the Dclk1-expressing cells were not increased in the antrum. Although we did observe a marked increase in Dclk1-positive tuft cells in association with parietal cell loss and the development of spasmolytic polypeptide-expressing metaplasia (SPEM), the precise origin of Dclk1-expressing cells in the stomach remains largely unknown.Herein, we hypothesized that the number of Dclk1-expressing cells may be increased in association with parietal cell loss. We investigated the dynamics of Dclk1-expressing cells in several mouse models of oxyntic atrophy using acute treatment with DMP-777 or L-635, which are parietal cell-specific protonophores and initiate SPEM after acute parietal cell loss,^10–12 and Helicobacter felis infection, a chronic model of SPEM with a strong inflammatory response.¹³ We also examined a model of spontaneous parietal cell loss and metaplasia in the Areg^–/– mouse, which is a unique mouse model for the induction of SPEM and progression of SPEM to intestinal metaplasia.¹⁴ Finally, we compared these findings with oxyntic atrophy and SPEM induced in insulin-gastrin (INS/GAS) transgenic mice¹³ as well as Gast^–/– mice, which demonstrate rapid induction of SPEM after 1 day of DMP-777 treatment.¹² In addition, we sought to identify the lineage of origin for tuft cells in the stomach using defined lineage mapping mouse strains. The results suggest that Dclk1-expressing cells are amplified in the setting of parietal cell loss and that the increase in tuft cells is driven by elevations in gastrin. More important, the Dclk1-expressing cells are rapidly lost from the mucosa on reestablishment of parietal cells and normal gastric lineages. These transiently presenting Dclk1-positive cells have a morphology that is distinct from normal tuft cells, suggesting that they represent a distinct class of sensory cells.