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SLE Serum Induces Altered Goblet Cell Differentiation and Leakiness in Human Intestinal Organoids

ABSTRACT: Human intestinal epithelial cells are the interface between luminal content and basally residing immune cells. They form a tight monolayer that constantly secretes mucus creating a multi-layered protective barrier. Alterations in this barrier can lead to increased permeability which is common in Systemic Lupus Erythematosus (SLE) patients. However, it remains unexplored how the barrier is affected. Here, we present an in vitro model specifically designed to examine the effects of SLE on epithelial cells. We utilize human colon organoids that are stimulated with serum from SLE patients. Combining transcriptomic with functional analyses revealed that SLE serum induced an expression profile marked by a reduction of goblet cell markers and changed mucus composition. Additionally, organoids exhibited imbalanced cellular composition along with enhanced permeability, altered mitochondrial function, and an interferon gene signature. Similarly, transcriptomic analysis of SLE colon biopsies revealed a downregulation of secretory markers. Our work uncovers a crucial connection between SLE and intestinal homeostasis that might be promoted in vivo through the blood, offering insights into the causal connection of barrier dysfunction and autoimmune diseases.

SUBMITTER: Dr. Inga, Viktoria Hensel

PROVIDER: S-SCDT-10_1038-S44321-024-00023-3 | biostudies-other |

REPOSITORIES: biostudies-other

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SLE serum induces altered goblet cell differentiation and leakiness in human intestinal organoids.

Project description:Human intestinal epithelial cells are the interface between luminal content and basally residing immune cells. They form a tight monolayer that constantly secretes mucus creating a multilayered protective barrier. Alterations in this barrier can lead to increased permeability which is common in systemic lupus erythematosus (SLE) patients. However, it remains unexplored how the barrier is affected. Here, we present an in vitro model specifically designed to examine the effects of SLE on epithelial cells. We utilize human colon organoids that are stimulated with serum from SLE patients. Combining transcriptomic with functional analyses revealed that SLE serum induced an expression profile marked by a reduction of goblet cell markers and changed mucus composition. In addition, organoids exhibited imbalanced cellular composition along with enhanced permeability, altered mitochondrial function, and an interferon gene signature. Similarly, transcriptomic analysis of SLE colon biopsies revealed a downregulation of secretory markers. Our work uncovers a crucial connection between SLE and intestinal homeostasis that might be promoted in vivo through the blood, offering insights into the causal connection of barrier dysfunction and autoimmune diseases.

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IL-33 Induces Murine Intestinal Goblet Cell Differentiation Indirectly via Innate Lymphoid Cell IL-13 Secretion.

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Interleukin-4 Promotes Tuft Cell Differentiation and Acetylcholine Production in Intestinal Organoids of Non-Human Primate.

Project description:In the intestine, the innate immune system excludes harmful substances and invading microorganisms. Tuft cells are taste-like chemosensory cells found in the intestinal epithelium involved in the activation of group 2 innate lymphoid cells (ILC2). Although tuft cells in other tissues secrete the neurotransmitter acetylcholine (ACh), their function in the gut remains poorly understood. In this study, we investigated changes in the expression of genes and cell differentiation of the intestinal epithelium by stimulation with interleukin-4 (IL-4) or IL-13 in macaque intestinal organoids. Transcriptome analysis showed that tuft cell marker genes were highly expressed in the IL-4- and IL-13-treated groups compared with the control, and the gene expression of choline acetyltransferase (ChAT), a synthesis enzyme of ACh, was upregulated in IL-4- and IL-13-treated groups. ACh accumulation was observed in IL-4-induced organoids using high-performance liquid chromatography-mass spectrometry (HPLC/MS), and ACh strongly released granules from Paneth cells. This study is the first to demonstrate ACh upregulation by IL-4 induction in primates, suggesting that IL-4 plays a role in Paneth cell granule secretion via paracrine stimulation.

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Isx-9 induces enteroendocrine cell differentiation in the intestinal organoids

Project description:We investigated the cell identity and cell proportion in the intestinal organoids treated by Isoxazole-9 (Isx-9) using single-cell transcriptome analysis. Isx-9 enriches enteroendocrine cells without altering the cell identity of other lineages. To investigate the mechanism of this process, we performed RNA-seq and ATAC-seq of Isx-9 treated intestinal stem cells. Based on the gene expression pattern and differential peaks of open chromatin, we found that Isx-9 upregulated neuroendocrine related genes, and elevated the chromatin accessibility at the promoter region of enteroendocrine related transcription factors.

2023-09-05 | GSE183476 | GEO

Culture and differentiation of rabbit intestinal organoids and organoid-derived cell monolayers.

Project description:Organoids emulate many aspects of their parental tissue and are therefore used to study pathogen-host interactions and other complex biological processes. Here, we report a robust protocol for the isolation, maintenance and differentiation of rabbit small intestinal organoids and organoid-derived cell monolayers. Our rabbit intestinal spheroid and monolayer cultures grew most efficiently in L-WRN-conditioned medium that contained Wnt, R-spondin and Noggin, and that had been supplemented with ROCK and TGF-β inhibitors. Organoid and monolayer differentiation was initiated by reducing the concentration of the L-WRN-conditioned medium and by adding ROCK and Notch signalling inhibitors. Immunofluorescence staining and RT-qPCR demonstrated that our organoids contained enterocytes, enteroendocrine cells, goblet cells and Paneth cells. Finally, we infected rabbit organoids with Rabbit calicivirus Australia-1, an enterotropic lagovirus that-like many other caliciviruses-does not grow in conventional cell culture. Despite testing various conditions for inoculation, we did not detect any evidence of virus replication, suggesting either that our organoids do not contain suitable host cell types or that additional co-factors are required for a productive infection of rabbit organoids with Rabbit calicivirus Australia-1.

| S-EPMC7940483 | biostudies-literature

Zebrafish Agr2 is required for terminal differentiation of intestinal goblet cells.

Project description:BackgroundMammalian Anterior Gradient 2 (AGR2) is a protein disulfide isomerase that is required for the production of intestinal mucus and Paneth and goblet cell homeostasis. However, whether increased endoplasmic reticulum (ER) stress occurs in Agr2(-/-) mice remains a controversial issue.Methodology/principal findingsWe characterized the function of zebrafish agr2 by both morpholino antisense oligomer-mediated knockdown and agr2 mRNA overexpression. Fluorescent whole-mount double in situ hybridization indicated that in the intestine, agr2 was only expressed in goblet cells. Significantly increased numbers of immature Alcian blue-stained goblet cells were observed in the intestines of 104- and 120-hours post fertilization (hpf) agr2 morphants. Transmission electron microscopy analyses further confirmed the existence of immature pre-goblet cells containing few mucous granules in the mid-intestines of 104- and 120-hpf agr2 morphants. agr2 expression was not significantly induced by an ER stress inducer, tunicamycin. Expression of the ER chaperone gene hspa5, the spliced form of xbp1s, c/enhancer binding protein homologous protein chop, and the activating transcription factor 4b1 atf4b1 were not significantly induced in either 104-hpf agr2 morphants or agr2-overexpressed embryos. Similar percentages of P-Histone H3-stained M phase cells were identified in intestines of 104-hpf agr2 morphants and control embryos.Conclusions/significanceOur study demonstrates that in contrast to mouse AGR2, zebrafish Agr2 is expressed in only one intestinal secretory cell type - the goblet cells. Agr2 is essential for terminal differentiation of intestinal goblet cells in zebrafish embryos. Either knockdown of agr2 function or agr2 overexpression could not extensively induce expression of members of the unfolded protein response pathway.

| S-EPMC3326001 | biostudies-literature

Intestinal Neurogenin 3 directs differentiation of a bipotential secretory progenitor to endocrine cell rather than goblet cell fate.

Project description:Neurogenin 3 is essential for enteroendocrine cell development; however, it is unknown whether this transcription factor is sufficient to induce an endocrine program in the intestine or how it affects the development of other epithelial cells originating from common progenitors. In this study, the mouse villin promoter was used to drive Neurogenin 3 expression throughout the developing epithelium to measure the affect on cell fate. Although the general morphology of the intestine was unchanged, transgenic founder embryos displayed increased numbers of cells expressing the pan-endocrine marker chromogranin A. Accordingly, expression of several hormones and pro-endocrine transcription factors was increased in the transgenics suggesting that Neurogenin 3 stimulated a program of terminal enteroendocrine cell development. To test whether increased endocrine cell differentiation affected the development of other secretory cell lineages, we quantified goblet cells, the only other secretory cell formed in embryonic intestine. The Neurogenin 3-expressing transgenics had decreased numbers of goblet cells in correspondence to the increase in endocrine cells, with no change in the total secretory cell numbers. Thus, our data suggest that Neurogenin 3 can redirect the differentiation of bipotential secretory progenitors to endocrine rather than goblet cell fate.

| S-EPMC2679162 | biostudies-literature

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