Tuft cells act as regenerative stem cells in the human intestine
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE233451 | GEO | 2024/05/01
REPOSITORIES: GEO
Similar Datasets
Project description:The intestinal epithelium is our first line of defense against infections of the gut and the plasticity in cellular differentiation of the intestinal epithelium is an important part of this response. The changes in cellular composition is driven by immune cell derived cytokines. Here we investigate the response over time upon stimulation with 10 ng/mL of the cytokine Interleukin-13 (IL-13). The intestinal organoids were lyzed 48 hours after splitting and IL-13 was added 24h, 8h, 4h and 1h before lysis. Furthermore, we have found BMP signaling to be important in regulating the cellular differentiation induced by IL-13. We therefore added added a combination treatment with the activin receptor-like kinase 2 (ALK-2) signaling inhibitor Dorsomorphin homolog 1 (DMH1) in concentration of 5 uM in some samples 24 hours before lysis. We find that ALK-2 signaling is crucial for IL-13 driven Tuft cell differentiation.
2022-05-08 | E-MTAB-10455 | biostudies-arrayexpress
Project description:The intestinal epithelium is our first line of defense against infections of the gut and the plasticity in cellular differentiation of the intestinal epithelium is an important part of this response. The changes in cellular composition is driven by immune cell derived cytokines. Here we use signature cytokines of different type of immune responses applied to small intestinal organoids to model how different immune responses affect intestinal epithelial development. Simplified, IL-13 represents type II immunity against infections such as parasites and IL-22 represents type III immunity against infections such as extracellular bacterial infections. 10 ng/mL of IL-13 and IL-22 was added for 72 hours after splitting. Furthermore, we have found BMP signaling to be important in regulating the cellular differentiation induced by IL-13. We therefore added added a combination treatment with the activin receptor-like kinase 2 (ALK-2) signaling inhibitor Dorsomorphin homolog 1 (DMH1) in concentration of 5 uM. We find that ALK-2 signaling is crucial for IL-13 driven Tuft cell differentiation.
2022-05-08 | E-MTAB-9185 | biostudies-arrayexpress
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:Interferon lambdas (IFN-λs) are crucial to control virus infections at mucosal surfaces. Interleukin-22 (IL-22) was reported to help IFN-λ control rotavirus infection in mice either by aiding in the induction of interferon stimulated genes (ISGs) or by increasing cell proliferation thereby clearing virally infected cells. We investigated whether IL-22 and IFN-λs exhibited similar synergistic effects in human intestinal epithelial cells models. Our results showed that co-treatment of IL-22 and IFN-λ induced more phosphorylation of STAT1 than either cytokine used alone. However, this increased STAT1 activation did not translate to increased ISG production or antiviral protection. Transcriptomics analysis revealed that despite sharing a receptor and activating the similar STATs, the signaling generated by IL-22 and IFN-λs is independent where IFN-λs signaling induces ISGs and IL-22 signaling induces cell proliferation genes. Using human intestinal organoids, we confirmed that IL-22 increased the size of the organoids due to increased cell proliferation and increasing the stem cell marker (OLFM4). These findings suggest that in human intestinal cells, IFN-λs and IL-22 act independently to clear virus infections. IFN-λs induce ISGs to control virus replication and spread while IL-22 increases cell proliferation to eliminate infected cells and repair the damage epithelium. Although, these two cytokines do not increase each other’s function, they each play a key role in protecting human intestinal epithelium cells.
2023-12-30 | GSE243230 | 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:An inverse correlation between countries endemic for helminth infestation and Crohn's disease (CD) incidences has been reinforced by anecdotal but successful cases of helminth therapy for CD. Recent studies have revealed that tuft cells in the small intestine are critical for sensing helminths and directing a type 2 immune response to counteract colonization. Here, we establish an inverse relationship between chemosensory tuft cells and local tissue inflammation in CD patients as well as an established mouse model of TNF-á-induced Crohn's-like ileitis (TNFÄARE). Using a combination of mouse and organoid models, single-cell RNA-sequencing, multiplex immunofluorescence, computational analysis, metabolite mass spectrometry, and microbiome sequencing and manipulation, we identified Atonal Homolog 1 (ATOH1)-independent tuft cells, as opposed to ATOH1-dependent tuft cells, to be responsive to the commensal microbiome through the tricarboxylic acid (TCA) cycle metabolite succinate. To evaluate the ability of the malleable, ATOH1-independent tuft cell population to suppress intestinal inflammation, we administered succinate to TNFÄARE animals post onset of ileal inflammatory disease. We observed significantly reduced pathology that is exquisitely dependent on succinate-induced tuft cell specification in the disease model, leading to an anti-helminth response previously shown to suppress inflammation. Inflammation suppression was triggered by cytokines critical to anti-helminthic response, such as IL-22, IL-25, and IL-13. We provide evidence implicating the modulatory role of intestinal tuft cells in chronic intestinal inflammation, which could enable the development of CD therapies around leveraging this rare and elusive cell type.
2020-08-24 | GSE145829 | GEO
Project description:An inverse correlation between countries endemic for helminth infestation and Crohn's disease (CD) incidences has been reinforced by anecdotal but successful cases of helminth therapy for CD. Recent studies have revealed that tuft cells in the small intestine are critical for sensing helminths and directing a type 2 immune response to counteract colonization. Here, we establish an inverse relationship between chemosensory tuft cells and local tissue inflammation in CD patients as well as an established mouse model of TNF-á-induced Crohn's-like ileitis (TNFÄARE). Using a combination of mouse and organoid models, single-cell RNA-sequencing, multiplex immunofluorescence, computational analysis, metabolite mass spectrometry, and microbiome sequencing and manipulation, we identified Atonal Homolog 1 (ATOH1)-independent tuft cells, as opposed to ATOH1-dependent tuft cells, to be responsive to the commensal microbiome through the tricarboxylic acid (TCA) cycle metabolite succinate. To evaluate the ability of the malleable, ATOH1-independent tuft cell population to suppress intestinal inflammation, we administered succinate to TNFÄARE animals post onset of ileal inflammatory disease. We observed significantly reduced pathology that is exquisitely dependent on succinate-induced tuft cell specification in the disease model, leading to an anti-helminth response previously shown to suppress inflammation. Inflammation suppression was triggered by cytokines critical to anti-helminthic response, such as IL-22, IL-25, and IL-13. We provide evidence implicating the modulatory role of intestinal tuft cells in chronic intestinal inflammation, which could enable the development of CD therapies around leveraging this rare and elusive cell type.
2020-08-24 | GSE145828 | GEO
Project description:An inverse correlation between countries endemic for helminth infestation and Crohn's disease (CD) incidences has been reinforced by anecdotal but successful cases of helminth therapy for CD. Recent studies have revealed that tuft cells in the small intestine are critical for sensing helminths and directing a type 2 immune response to counteract colonization. Here, we establish an inverse relationship between chemosensory tuft cells and local tissue inflammation in CD patients as well as an established mouse model of TNF-á-induced Crohn's-like ileitis (TNFÄARE). Using a combination of mouse and organoid models, single-cell RNA-sequencing, multiplex immunofluorescence, computational analysis, metabolite mass spectrometry, and microbiome sequencing and manipulation, we identified Atonal Homolog 1 (ATOH1)-independent tuft cells, as opposed to ATOH1-dependent tuft cells, to be responsive to the commensal microbiome through the tricarboxylic acid (TCA) cycle metabolite succinate. To evaluate the ability of the malleable, ATOH1-independent tuft cell population to suppress intestinal inflammation, we administered succinate to TNFÄARE animals post onset of ileal inflammatory disease. We observed significantly reduced pathology that is exquisitely dependent on succinate-induced tuft cell specification in the disease model, leading to an anti-helminth response previously shown to suppress inflammation. Inflammation suppression was triggered by cytokines critical to anti-helminthic response, such as IL-22, IL-25, and IL-13. We provide evidence implicating the modulatory role of intestinal tuft cells in chronic intestinal inflammation, which could enable the development of CD therapies around leveraging this rare and elusive cell type.
2020-08-24 | GSE145827 | GEO
Project description:While the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5+ dysplastic regions after influenza injury. Using bulk and single cell transcriptomics, we characterized and delineated multiple distinct tuft cell populations that arise following influenza clearance. Distinct from intestinal tuft cells which rely on Type 2 immune signals for their expansion, neither IL-25 nor IL-4Ra signaling are required to drive tuft cell development in dysplastic/injured lungs. Furthermore, tuft cells were also observed upon bleomycin injury, suggesting that their development may be a general response to severe lung injury. While intestinal tuft cells promote growth and differentiation of surrounding epithelial cells, in the lungs of tuft cell deficient mice, Krt5+ dysplasia still occurs, goblet cell production is unchanged, and there remains no appreciable contribution of Krt5+ cells into more regionally appropriate alveolar Type 2 cells. Together, these findings highlight unexpected differences in signals necessary for lung tuft cell amplification and establish a framework for future elucidation of tuft cell functions in pulmonary health and disease.
2022-09-14 | GSE197162 | GEO
Project description:While the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5+ dysplastic regions after influenza injury. Using bulk and single cell transcriptomics, we characterized and delineated multiple distinct tuft cell populations that arise following influenza clearance. Distinct from intestinal tuft cells which rely on Type 2 immune signals for their expansion, neither IL-25 nor IL-4Ra signaling are required to drive tuft cell development in dysplastic/injured lungs. Furthermore, tuft cells were also observed upon bleomycin injury, suggesting that their development may be a general response to severe lung injury. While intestinal tuft cells promote growth and differentiation of surrounding epithelial cells, in the lungs of tuft cell deficient mice, Krt5+ dysplasia still occurs, goblet cell production is unchanged, and there remains no appreciable contribution of Krt5+ cells into more regionally appropriate alveolar Type 2 cells. Together, these findings highlight unexpected differences in signals necessary for lung tuft cell amplification and establish a framework for future elucidation of tuft cell functions in pulmonary health and disease.
2022-09-14 | GSE197156 | GEO