Spatial transcriptomic studies of the colon from a wildtype mouse
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE210973 | GEO | 2023/12/31
REPOSITORIES: GEO
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Project description:Dclk1 expression defines a rare population of cells in normal pancreas whose frequency is increased at early stages pancreatic tumors. The identity and the precise roles of Dclk1 expressing cells in pancreas are matter of debate, although the concept of their involvement in a number of key functions, including regeneration and neoplasia, has emerged. We employed a novel Dclk1 reporter mouse model and single cell RNAseq analysis to define Dclk1 expressing cells in normal pancreas and pancreatic neoplasia. In normal pancreas, Dclk1 epithelial expression identifies subsets of ductal, islet and acinar cells. In pancreatic neoplasia, Dclk1 expression identifies five epithelial cell populations, among which acinar-to-ductal metaplasia (ADM)-like cells and tuft-like cells represent the main ones. These cells play opposing roles in pancreatic neoplasia, with Dclk1+ ADM-like cells sustaining tumor growth and Dclk1+ tuft-like cells restraining tumor progression. The differentiation of Kras mutant acinar cells into Dclk1+ tuft-like cells requires the activation of SPIB and is further supported by a cellular loop involving cancer group 2 innate lymphoid cells (ILC2) and activated fibroblasts (CAFs) that provide IL13 and IL33, respectively. In turn, Dclk1+ tuft-like cells release angiotensinogen that play protective roles against pancreatic neoplasia. Overall, our study provides novel insights on the biology of Dclk1+ cells in normal pancreas and also unveils a protective axis against pancreatic neoplasia involving Dclk1+ tuft-like cells, ILC2 and CAFs, which ultimately results in angiotensinogen release.
2024-10-08 | GSE259357 | GEO
Project description:Dclk1 expression defines a rare population of cells in normal pancreas whose frequency is increased at early stages pancreatic tumors. The identity and the precise roles of Dclk1 expressing cells in pancreas are matter of debate, although the concept of their involvement in a number of key functions, including regeneration and neoplasia, has emerged. We employed a novel Dclk1 reporter mouse model and single cell RNAseq analysis to define Dclk1 expressing cells in normal pancreas and pancreatic neoplasia. In normal pancreas, Dclk1 epithelial expression identifies subsets of ductal, islet and acinar cells. In pancreatic neoplasia, Dclk1 expression identifies five epithelial cell populations, among which acinar-to-ductal metaplasia (ADM)-like cells and tuft-like cells represent the main ones. These cells play opposing roles in pancreatic neoplasia, with Dclk1+ ADM-like cells sustaining tumor growth and Dclk1+ tuft-like cells restraining tumor progression. The differentiation of Kras mutant acinar cells into Dclk1+ tuft-like cells requires the activation of SPIB and is further supported by a cellular loop involving cancer group 2 innate lymphoid cells (ILC2) and activated fibroblasts (CAFs) that provide IL13 and IL33, respectively. In turn, Dclk1+ tuft-like cells release angiotensinogen that play protective roles against pancreatic neoplasia. Overall, our study provides novel insights on the biology of Dclk1+ cells in normal pancreas and also unveils a protective axis against pancreatic neoplasia involving Dclk1+ tuft-like cells, ILC2 and CAFs, which ultimately results in angiotensinogen release.
2024-10-08 | GSE259356 | GEO
Project description:(1) Background: Knockout (KO) of heterogeneous nuclear ribonucleoprotein I (Hnrnp I) in mouse intestinal epithelial cells (IECs) induced a severe inflammatory response in the colon, followed by hyperproliferation. This study aimed to investigate the epithelial lineage dynamics and cell–cell communications that underlie inflammation and colitis. (2) Methods: Single cells were isolated from the colons of wildtype (WT) and KO mice and used in scRNA−seq. Whole colons were collected for immunofluorescence staining and cytokine assays. (3) Results: from scRNA−seq, the number of DCLK1 + colonic tuft cells was significantly higher in the Hnrnp I KO mice compared to the WT mice. This was confirmed by immunofluorescent staining of DCLK1. The DCLK1 + colonic tuft cells in KO mice developed unique communications with lymphocytes via interactions between surface L1 cell adhesion molecule (L1CAM) and integrins. In the KO mice colons, a significantly elevated level of inflammatory cytokines IL4, IL6, and IL13 were observed, which marks type−2 immune responses directed by group 2 innate lymphoid cells (ILC2s). (4) Conclusions: This study demonstrates one critical cellular function of colonic tuft cells, which facilitates type−2 immune responses by com-municating with ILC2s via the L1CAM–integrins interaction. This communication promotes pro−inflammatory signaling pathways in ILC2, leading to the increased secretion of inflammatory cytokines.
2023-10-14 | GSE245188 | GEO
Project description:We previously identified Dclk1, a tuft cell marker, marks tumor stem cells (TSCs) in mouse intestinal tumors. In this study, we have identified IL17RB as a cell surface marker distinctively expressed by Dclk1+ tuft-like tumor cells in mouse intestinal tumors. Using this tuft cell marker, we compared and analyzed the transcriptome of Lgr5-tuft marker-, Lgr5+tuft marker-, Lgr5-tuft marker+, and Lgr5+tuft marker+ tumor cells. These analyses revealed that tuft-like tumor cells in the intestinal tumors comprise two distinct subsets: highly differentiated tuft-like tumor cells (Lgr5-tuft marker+ cells) and tuft-like tumor cells with TCS potential (Lgr5+tuft marker+ cells).
2021-02-19 | GSE118853 | GEO
Project description:DDX5, a DEAD box containing RNA binding protein, is involved in multiple aspects of RNA metabolism and is abundantly expressed in all subsets of the intestinal epithelial cells (IEC). Here, we characterized the DDX5-dependent transcriptome in the small intestine. In the DDX5△IEC tissue, we found that secretory IEC lineage progenitor containing spots (Atoh1hi and Sox4hi) had reduced expression of Pou2f3, a master regulator of a subset of IECs called tuft cells. As a result of the loss of Pou2f3 expression in the progenitors, DDX5△IEC tissue harbored lower number of tuft cell containing spots (Dclk1hi) compare to WT tissues.
2021-12-03 | GSE184564 | GEO
Project description:In our study, we investigated the effect of muscarinic receptor blockade on murine intestinal stem cell activity and differentiation. Following pharmacologic (scopolamine) and genetic muscarinic receptor interruption (M3R-KO, M1R-KO; Vil-Cre x M3R fl/fl, Vil-Cre x M1R fl/fl mice, respectively), we observe a selective, significant expansion of DCLK1-positive tuft cells. This is primarily sensed by endocrine Prox1-positive cells (Prox1-CreERT2 x M3R fl/fl mice), while Lgr5-positive ISCs respond with a reduction of their cellular activity (Lgr5-EGFP-IRES-CreERT2 x M3R fl/fl mice). To characterize expanding tuft cells in more detail, adult BAC transgenic DCLK1-DTR-ZSgreen reporter mice generated in our lab were treated with scopolamine or sodium chloride as controls (Sham) for 7d and live jejunal EPC-positive/ZSgreen-positive cells sorted. Extracted total RNA from sorted ZSgreen-positive cells of scopolamine- and sham-treated mice was sequenced. Further analysis revealed that expanding tuft cells orchestrate an increase in mucosal acetylcholine, which maintained intracellular signaling pathways such as p-ERK/ERK 1/2 or TCF-1/7. Finally, acute irradiation injury was employed to investigate the importance of this regulatory circuit for tissue homeostasis. Indeed, tissue injury in Vil-Cre x M3R fl/fl mice resulted in a severe reduction of epithelial DCLK1-positive tuft cells, concomitant to reduced mucosal Ach levels as well as intracellular PI3K-/p-ERK levels. Therefore, DCLK1-positive tuft cells appear essential for the maintenance of a regular intestinal cholinergic niche.
2019-11-01 | GSE138365 | GEO
Project description:Tuft cells are an epithelial cell subset critical for initiating type 2 immune responses to parasites and protozoa in the small intestine. To respond to these stimuli, intestinal tuft cells use taste chemosensory signaling pathways, but the role of taste receptors in type 2 immunity is poorly understood. Here, we show that the taste receptor TAS1R3, which detects sweet and umami in the tongue, also regulates tuft cell responses in the distal small intestine. BALB/c mice, which have an inactive form of TAS1R3, as well as Tas1r3-deficient C57BL6/J mice both have severely impaired responses to tuft cell-inducing signals in the ileum including the protozoa Tritrichomonas muris and succinate. In contrast, TAS1R3 is not required to mount an immune response to the helminth Heligmosomoides polygyrus, which infects the proximal small intestine. Examination of uninfected Tas1r3-/- mice revealed a modest reduction in the number of tuft cells in the proximal small intestine but a severe decrease in the distal small intestine at homeostasis. Together, these results suggest that TAS1R3 influences intestinal immunity by shaping the epithelial cell landscape at steady state.
2020-01-09 | GSE140395 | GEO
Project description:The olfactory neuroepithelium serves as a sensory organ for odors and forms part of the nasal mucosal barrier. Olfactory sensory neurons are surrounded and supported by epithelial cells. Among them, microvillous cells (MVCs) are strategically positioned at the apical surface, but their specific functions are enigmatic and their relationship to the other specialized epithelial cells, particularly the solitary chemosensory cell family, is unclear. Here, we establish that the family of MVCs comprises tuft cells and ionocytes in both mice and humans. Integrating analysis of the respiratory and olfactory epithelia, we define the unique receptor expression of TRPM5+ tuft-MVCs compared to Gɑ-gustducinhigh respiratory tuft cells and characterize a new population of glandular DCLK1+ tuft cells. To establish how allergen sensing by tuft-MVCs might direct olfactory mucosal responses, we employed an integrated single-cell transcriptional and protein analysis. Inhalation of Alternaria induced mucosal epithelial effector molecules including Chil4, and a distinct pathway leading to proliferation of the quiescent olfactory horizontal basal stem cell (HBC) pool, both triggered in the absence of olfactory apoptosis. While the Chil4 pathway was dependent on STAT6 signaling and innate lymphocytes, neither were required for HBC proliferation. Alternaria- and ATP- elicited HBC proliferation was dependent on tuft-MVCs, establishing these specialized epithelial cells as regulators of olfactory stem cell responses. Together our data provide high resolution characterization of nasal tuft cell heterogeneity and uncover a novel function for TRPM5+ tuft-MVCs in directing the olfactory mucosal response to allergens.
2023-12-04 | GSE245074 | GEO
Project description:Intestinal homeostasis is dynamically coordinated by various types of epithelial cells fulfilling their specific functions. Tuft cells as chemosensory cells have emerged as key players of the host response, such as innate immunity. Tuft cells are also critical for the restoration of intestinal architecture upon damage, thereby contributing to inflammatory bowel diseases (IBDs) characterized by defective intestinal barrier integrity. However, the molecular mechanism of how tuft cell homeostasis is controlled remains obscure. Recent studies have identified single-nucleotide polymorphisms in the inositol polyphosphate multikinase (IPMK) gene associated with IBD predisposition. IPMK, an essential enzyme for inositol phosphate metabolism, has been known to mediate major biological events such as growth. To investigate the functional significance of IPMK in gut epithelium, we generated intestinal epithelial cell (IEC)-specific Ipmk knockout (IPMKΔIEC) mice. Whereas IPMKΔIEC mice developed normally and showed no intestinal abnormalities during homeostasis, Ipmk deletion aggravated dextran sulfate sodium (DSS)-induced colitis, with higher clinical colitis scores, and elevated epithelial barrier permeability. Surprisingly, no apparent defects in epithelial growth signaling pathway and inflammation were found in DSS-challenged, IPMK-deficient colons. Rather, Ipmk deletion led to a significant decrease in the number of tuft cells without influencing other intestinal epithelial cells. Ipmk deletion in the gut epithelium was found to reduce choline acetyltransferase but not cytokines (e.g., IL-25), suggesting selective loss of cholinergic signaling. Single-cell RNA-sequencing of mouse colonic tuft cells (EpCAM+/Siglec F+) and immunohistochemistry revealed three populations of tuft cells and further showed that, in IPMKΔIEC mice, a transcriptionally inactive tuft club cell population was markedly expanded, and neuronal-related tuft cells were relatively decreased, supporting the abnormal development of tuft cells without IPMK functions. Thus, IPMK acts as a physiological determinant of colonic tuft cell homeostasis, thereby mediating tissue regeneration upon injury.
2022-10-26 | GSE200284 | GEO
Project description:Purpose: To examine the temporal changes in intestinal tuft cell number and activity in response to intake of a high fat diet and investigate the relation to whole-body energy metabolism and the immune phenotype of the small intestine and epididymal white adipose tissue (eWAT). Methods: C57BL/6J mice were fed either a low fat reference diet (RFD, 10 % kcal fat) or a high fat diet (HFD, 60% kcal fat) for 9 or 22 weeks, followed by characterization of whole-body metabolic parameters, transcription profiles of sorted intestinal tuft cells, and immune phenotypes of tissues. Results: HFD feeding was associated with reductions in the overall number of small intestinal epithelial cells and tuft cells and reduced expression of the intestinal type 2 tuft cell markers Il25 and Tslp. Amongst >1,700 diet-regulated genes in tuft cells identified by RNA-seq, we observed an early association between body mass expansion and increased expression of Serpini1, which encodes the serine protease inhibitor neuroserpin. By contrast, tuft cell expression of genes encoding the GABA-receptors linked to reduced body mass gain. Although we observed a HFD-induced change in the eWAT inflammatory profile, the small intestinal lamina propria displayed a consistent non-inflammatory phenotype, and small intestinal tuft cell-derived transcripts were found to correlate with whole body metabolic features independently of intestinal immune cell involvement. Conclusion: Our These findings point to a role for small intestinal tuft cells in systems-wide metabolic regulation.
2019-11-26 | GSE141002 | GEO