Optimal human intestinal organoid model reveals interleukin-22-induced Paneth cell differentiation
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ABSTRACT:
PROVIDER: PRJNA782988 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17018316_1.fastq.gz | Fastqsanger.gz | |||
| SRR17018316_2.fastq.gz | Fastqsanger.gz | |||
| SRR17018317_1.fastq.gz | Fastqsanger.gz | |||
| SRR17018317_2.fastq.gz | Fastqsanger.gz |
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Project description:Here, we developed an optimal system for culturing human small intestinal organoids (hSIOs) that recapitulate the structural and functional complexity of the intestinal crypt in vitro, including mature Paneth cells. With this model, we found that IL-22 is required for the differentiation of human Paneth cells. Rather than STAT3, the PI3K-mTORC1 axis, downstream of IL-22, mediates Paneth cell differentiation programs. CD-associated variants of the IL-22 receptor (IL10RB) were introduced in our system, resulting in the abolishment of Paneth cells in hSIOs. Moreover, our data demonstrated that long-term IL-22 exposure inhibited the growth of hSIOs, challenging the current perception of IL-22 in promoting intestinal regeneration, but rather in reducing cell viability. As a proof-of-principle, our study demonstrates that this optimal culture system for hSIOs has great potential for modelling human intestinal physiology and pathophysiology.
2022-08-23 | GSE189423 | GEO
Project description:Opposing roles have been proposed for IL-22 in intestinal pathophysiology. We have optimized human small intestinal organoid (hSIO) culturing, constitutively generating all differentiated cell types while maintaining an active stem cell compartment. IL-22 does not promote the expansion of stem cells but rather slows the growth of hSIOs. In hSIOs, IL-22 is required for formation of Paneth cells, the prime producers of intestinal antimicrobial peptides (AMPs). Introduction of inflammatory bowel disease (IBD)-associated loss-of-function mutations in the IL-22 co-receptor gene IL10RB resulted in abolishment of Paneth cells in hSIOs. Moreover, IL-22 induced expression of host defense genes (such as REG1A, REG1B, and DMBT1) in enterocytes, goblet cells, Paneth cells, Tuft cells, and even stem cells. Thus, IL-22 does not directly control the regenerative capacity of crypt stem cells but rather boosts Paneth cell numbers, as well as the expression of AMPs in all cell types.
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Project description:Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease which leads to serious impairment of reproductive health in women of child-bearing age. Anovulation or oligo-ovulation is a common clinical manifestation of PCOS patients. The disturbance of ovarian immune microenvironment contributes to the disorders of follicle development and ovulation, and the mechanism remains unclear. Here we demonstrated the protective effect of immune factor interleukin-22 (IL-22) on PCOS follicle development and ovulation. Follicular IL-22 levels were significantly lower in PCOS patients than in the control group and were positively correlated with the oocyte fertilization rate and the high-quality embryo rate. Additionally, IL-22 evidently improved follicle development in vitro and promoted ovulation-related gene expression, which was disrupted by the depletion of interleukin-22 receptor 1 (IL-22R1) or inhibition of STAT3 in granulosa cells, indicating that IL-22 acted through IL-22R1 and STAT3 signalling pathway to promote follicle development and ovulation in PCOS. In summary, this study elucidated the vital role of ovarian immune microenvironment in follicle development and ovulation, the application of IL-22 may provide new insights into the treatment of PCOS patients.
2024-10-09 | GSE266340 | GEO
Project description:Interleukin (IL) - 22 is a cytokine that plays a critical role in the maintenance of intestinal epithelial homeostasis. Its downstream functions are mediated through ligation of its heterodimeric receptor comprised of IL-22 receptor subunit alpha 1 (IL-22Ra1) and IL-10R2, and subsequent activation of signal transducer and activator of transcription 3 (STAT3). IL-22 signaling can induce genes necessary for intestinal epithelial cell proliferation, tissue regeneration, tight junction fortification, and production of antimicrobials. Emerging studies have also implicated IL-22 signaling in the regulation of intestinal epithelial fucosylation in mice. However, whether IL-22 regulates intestinal fucosylation in human intestinal epithelial cells and the molecular mechanisms that govern this process are unknown. Here, we show that IL-22 signaling regulates expression of the B3GNT7 transcript, which encodes a β1-3-N-acetylglucosaminyltransferase that can participate in the synthesis of poly-N-acetyllactosamine (LacNAc) chains. Additionally, we show that IL-22 signaling regulates levels of the a1-3-fucosylated Lewis X (Lex) blood group antigen and this glycan epitope is primarily displayed on heavily O-glycosylated intestinal epithelial glycoproteins. The IL-22-mediated increase in Lex antigen levels requires B3GNT7, as disruption of B3GNT7 expression moderated the IL-22-dependent increase in Lex antigen levels. Moreover, we show that increased expression of B3GNT7 alone is sufficient to promote increased display of Lex-decorated carbohydrate glycan structures primarily on O-glycosylated intestinal epithelial glycoproteins. Together, the data presented here identify B3GNT7 as a critical intermediary in IL-22-dependent induction of intestinal fucosylation of O-linked glycans and uncover a novel role for B3GNT7 in intestinal glycosylation.
2021-11-27 | GSE154889 | GEO
Project description:T cells are key players in immunosurveillance and anti-tumor immunity. However, subsets of T helper cells producing high levels of interleukin-22 (IL-22) accumulate in primary breast and lung tumors and are linked to a more dismal outcome. Here, we demonstrate that such TH22 cells promote metastasis by abrogating NK cell-mediated immune surveillance. Using mouse models of metastatic lung and breast cancer, we find that secreted IL-22 acts directly on disseminated cancer cells expressing the IL-22 receptor (IL-22R). In turn, IL-22 induces cancer cell overexpression of CD155, which binds to activating receptor CD226 on the surface of NK cells and triggers its downregulation. This functionally impairs NK cells to promote lung metastases. Importantly, neutralization of IL-22 in vivo blocked the metastatic potential of cancer cells, suggestive of therapeutic exploitability. We confirmed the paramount role of IL-22 signaling that was associated with CD155 expression in human datasets and marked poor patient outcomes. This study reveals an immunosuppressive feedback loop activated by T cell-derived IL-22 in cancer progression, creating the rationale for the development of future targeted therapeutics.
2022-06-30 | GSE202314 | GEO
Project description:Homeostasis of self-renewing small intestinal crypts results from neutral competition between Lgr5 stem cells, small cycling cells located at crypt bottoms1, 2. Lgr5 stem cells are interspersed between terminally differentiated Paneth cells, that are known to produce bactericidal products such as lysozyme and cryptdins/defensins3. Single Lgr5-expressing stem cells can be cultured to form long-lived, self-organizing crypt-villus organoids in the absence of non-epithelial niche cells4. Here, we note a close physical association of Lgr5 stem cells with Paneth cells in vivo and in vitro. CD24+ Paneth cells express EGF, TGF?, Wnt3 and the Notch-ligand Dll4, all essential signals for stem cell maintenance in culture. Co-culturing of sorted stem cells with Paneth cells dramatically improves organoid formation. This Paneth cell requirement can be substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells in vivo results in the concomitant loss of Lgr5 stem cells. In colon crypts, CD24+ cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell. We used intestinal cell fractions from Lgr5-EGFP-ires-CreERT2 mice, expressing GFP under the control of the Lgr5 promoter. RNA was isolated from two FACS sorted cell populations: stem cells were sorted based on high level of GFP expression (GFPhi) and Paneth cells were sorted based on high level of CD24 expression (CD24hi) and high side-scatter (SSChi). Differentially labelled cRNA from GFPhi and CD24hi/SSChi cells from two different sorts (each combining ten individual mice) were hybridized on 4X44K Agilent Whole Mouse Genome dual colour Microarrays (G4122F) in two dye swap experiments, resulting in four individual arrays.
2010-11-29 | E-GEOD-25109 | biostudies-arrayexpress
Project description:Interleukin-22 (IL-22) regulates B3GNT7 expression to induce intestinal fucosylation of O-linked glycans
| PRJNA647688 | ENA
Project description:Homeostasis of self-renewing small intestinal crypts results from neutral competition between Lgr5 stem cells, small cycling cells located at crypt bottoms1, 2. Lgr5 stem cells are interspersed between terminally differentiated Paneth cells, that are known to produce bactericidal products such as lysozyme and cryptdins/defensins3. Single Lgr5-expressing stem cells can be cultured to form long-lived, self-organizing crypt-villus organoids in the absence of non-epithelial niche cells4. Here, we note a close physical association of Lgr5 stem cells with Paneth cells in vivo and in vitro. CD24+ Paneth cells express EGF, TGFα, Wnt3 and the Notch-ligand Dll4, all essential signals for stem cell maintenance in culture. Co-culturing of sorted stem cells with Paneth cells dramatically improves organoid formation. This Paneth cell requirement can be substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells in vivo results in the concomitant loss of Lgr5 stem cells. In colon crypts, CD24+ cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell.
2010-11-29 | GSE25109 | GEO
Project description:Paneth cells (PCs) are post-mitotic secretory cells of the small intestine that produce antimicrobials, growth factors, and cytokines. Multiple diseases have been linked to alterations in PC function. Past studies of PCs have relied on in vivo models, and limited in vitro models, including organoids. While useful, whether the in vitro models recapitulate in vivo biology is an important, yet unanswered question. Here, we present a bona fide in vitro PC-enriched population derived via chemically-induced (CI) differentiation of primary murine adult stem cells. We define the identity of PCs in our system and compare to PCs of established organoid systems and those found in vivo. Importantly, we demonstrate stimulant-induced and microbe-responsive antimicrobial function of our CI-PCs – hallmark functions of PCs in vivo. Thus, we define and produce the most physiologically-relevant in vitro PC population to date, providing a superior tool to study cellular development, host-microbe interactions, and inflammatory disease.
2018-04-02 | GSE100274 | GEO