STAT1 regulates immune-mediated intestinal stem cell proliferation and epithelial regeneration
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ABSTRACT:
PROVIDER: PRJNA1154957 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30502600_1.fastq.gz | Fastqsanger.gz | |||
| SRR30502600_2.fastq.gz | Fastqsanger.gz | |||
| SRR30502601_1.fastq.gz | Fastqsanger.gz | |||
| SRR30502601_2.fastq.gz | Fastqsanger.gz | |||
| SRR30502602_1.fastq.gz | Fastqsanger.gz |
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Project description:The role of the immune system in regulating tissue stem cells remains poorly understood, as does the relationship between immune-mediated tissue damage and regeneration. Graft vs. host disease (GVHD) occurring after allogeneic bone marrow transplantation (allo-BMT) involves immune-mediated damage to the intestinal epithelium and its stem cell compartment. To assess impacts of T-cell-driven injury on distinct epithelial constituents, we performed single cell RNA sequencing on intestinal crypts following experimental BMT. Intestinal stem cells (ISCs) from GVHD mice exhibited global transcriptomic changes associated with a substantial Interferon-γ response and upregulation of STAT1. To determine its role in crypt function, STAT1 was deleted within murine intestinal epithelium. Following allo-BMT, STAT1 deficiency resulted in reduced epithelial proliferation and impaired ISC recovery. Similarly, epithelial Interferon-γ receptor deletion also attenuated proliferation and ISC recovery post-transplant. Investigating the mechanistic basis underlying this epithelial response, ISC STAT1 expression in GVHD was found to correlate with upregulation of ISC c-Myc. Furthermore, activated T cells stimulated Interferon-γ- dependent epithelial regeneration in co-cultured organoids, and Interferon-γ directly induced STAT1-dependent c-Myc expression and ISC proliferation. These findings illustrate immunologic regulation of a core tissue stem cell program after damage and support a role for Interferon-γ as a direct contributor to epithelial regeneration.
2024-09-09 | GSE276126 | GEO
Project description:The role of the immune system in regulating tissue stem cells remains poorly understood, as does the relationship between immune-mediated tissue damage and regeneration. Graft vs. host disease (GVHD) occurring after allogeneic bone marrow transplantation (allo-BMT) involves immune-mediated damage to the intestinal epithelium and its stem cell compartment. To assess impacts of T-cell-driven injury on distinct epithelial constituents, we have performed single cell RNA sequencing on intestinal crypts following experimental BMT. Intestinal stem cells (ISCs) from GVHD mice have exhibited global transcriptomic changes associated with a substantial Interferon-γ response and upregulation of STAT1. To determine its role in crypt function, STAT1 has been deleted within murine intestinal epithelium. Following allo-BMT, STAT1 deficiency has resulted in reduced epithelial proliferation and impaired ISC recovery. Similarly, epithelial Interferon-γ receptor deletion has also attenuated proliferation and ISC recovery post-transplant. Investigating the mechanistic basis underlying this epithelial response, ISC STAT1 expression in GVHD has been found to correlate with upregulation of ISC c-Myc. Furthermore, activated T cells have stimulated Interferon-γ-dependent epithelial regeneration in co-cultured organoids, and Interferon-γ has directly induced STAT1-dependent c-Myc expression and ISC proliferation. These findings illustrate immunologic regulation of a core tissue stem cell program after damage and support a role for Interferon-γ as a direct contributor to epithelial regeneration.
| S-EPMC11697299 | biostudies-literature
Project description:Intestinal stem cells are required for proliferation, differentiation, and regeneration of the intestinal epithelium. Krüppel-like factor 5 regulates intestinal stem cells in both physiologic and pathological conditions and may be a treatment target in certain diseases of the intestine.
2021-10-27 | GSE131265 | GEO
Project description:The intestinal epithelial regeneration is driven by intestinal stem cells under homeostatic conditions. Differentiated intestinal epithelial cells, such as Paneth cells, are capable of acquiring multipotency and contributing to regeneration upon loss of intestinal stem cells. Paneth cells also support intestinal stem cell survival and regeneration. We report here that depletion of an RNA-binding protein named polypyrimidine tract binding protein 1 (PTBP1) in mouse intestinal epithelial cells causes intestinal stem cell death and epithelial regeneration failure. Mechanistically, we show that PTBP1 inhibits neuronal-like splicing programs in intestinal crypt cells, which is critical for maintaining intestinal stem cell stemness. This function is achieved at least in part through promoting the non-productive splicing of its paralog PTBP2. Moreover, PTBP1 inhibits the expression of an AKT inhibitor PHLDA3 in Paneth cells and permits AKT activation, which presumably maintains Paneth cell plasticity and function in supporting intestinal stem cell niche. We show that PTBP1 directly binds to a CU-rich region in the 3’ UTR of Phlda3, which we demonstrate to be critical for downregulating the mRNA and protein levels of Phlda3. Our results thus reveal the multifaceted in vivo regulation of intestinal epithelial regeneration by PTBP1 at the post-transcriptional level.
2023-01-18 | GSE185499 | 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:Establishment of intestinal organoid cultures modeling injuryassociated epithelial regeneration
| PRJNA693445 | ENA
Project description:Stringent regulation of the interferon signaling pathway is essential for maintaining the immune response to pathogens and tumors. The transcription factor STAT1 is a crucial mediator of this response. Here we show that hCAF1/CNOT7 regulates class I and II interferon pathways at different crucial steps. In resting cells hCAF1 can control STAT1 trafficking by interacting with the latent form of STAT1 in the cytoplasm. IFN treatment induces STAT1 release, suggesting that hCAF1 may shield cytoplasmic STAT1 from undesirable stimulation. Consistent, hCAF1 silencing enhances STAT1 basal promoter occupancy associated with increased expression of a subset of STAT1-regulated genes. Consequently, hCAF1 knockdown cells exhibit an increased protection against viral infection and reduced viral replication. Furthermore, hCAF1 participates in the extinction of the IFN signal, through its deadenylase activity, by speeding up the degradation of some STAT1-regulated mRNAs. Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumor escape. mRNAs from cells expressing the siRNA siRNA duplexes targeting hCAF1, corresponding to the coding region 941-961 (kd) (hCAF1 NCBI Reference Sequence: NM_013354.5) and one non-targeting control siRNA (mock).
2013-12-31 | E-GEOD-43334 | biostudies-arrayexpress
Project description:Uncontrolled inflammation drives tissue damage, highlighting the need for tightly regulated immune responses and tissue integrity, particularly in barrier tissues like the intestine. To maintain this exquisite balance, intestinal epithelial cells (IECs) employ molecular circuits that preserve tissue integrity following inflammation. STAT1 is traditionally viewed as a pro-inflammatory driver in the intestine, acting as a central signaling mediator downstream of interferons (IFN). Here, we identify threonine 748 (Thr748) phosphorylation of Stat1 as an evolutionarily conserved adaptation that reciprocally regulates IEC integrity and IFN responsiveness. Mice expressing a phospho-deficient T748A Stat1 mutant exhibit severe pathology similar to Stat1 deficient littermates, underscoring Thr748’s critical role in Stat1-driven protection following intestinal inflammation. Bone marrow transfer experiments further demonstrate that this protective effect is non-hematopoietic. Integrated genomic and transcriptomic analyses reveal that Thr748 phosphorylation modulates Stat1 DNA binding, directly activating the Itgb4 promoter and enhancing integrin β4 expression in IECs following inflamamtion. In vitro intestinal organoid models, combined with gain- and loss-of-function experiments, show that Stat1 promotes integrin β4 expression via Thr748 phosphorylation following damage, boosting epithelial resilience independently of IFN-induced Tyrosine 701 (Tyr701) phosphorylation. In contrast, IFN stimulation triggers Tyr701 phosphorylation of Stat1, upregulating Zbp1—a sensor of cytotoxic damage-associated nucleic acids—while suppressing integrin β4, leading to epithelial cytotoxicity, which is mitigated by Thr748 phosphorylation. Our findings uncover a modular architecture of Stat1 signaling that enables epithelial adaptation to damage, with Thr748 phosphorylation acting as a rheostat to preserve tissue integrity while restricting IFN-mediated cytotoxicity.
2025-07-09 | GSE297456 | GEO
Project description:Uncontrolled inflammation drives tissue damage, highlighting the need for tightly regulated immune responses and tissue integrity, particularly in barrier tissues like the intestine. To maintain this exquisite balance, intestinal epithelial cells (IECs) employ molecular circuits that preserve tissue integrity following inflammation. STAT1 is traditionally viewed as a pro-inflammatory driver in the intestine, acting as a central signaling mediator downstream of interferons (IFN). Here, we identify threonine 748 (Thr748) phosphorylation of Stat1 as an evolutionarily conserved adaptation that reciprocally regulates IEC integrity and IFN responsiveness. Mice expressing a phospho-deficient T748A Stat1 mutant exhibit severe pathology similar to Stat1 deficient littermates, underscoring Thr748’s critical role in Stat1-driven protection following intestinal inflammation. Bone marrow transfer experiments further demonstrate that this protective effect is non-hematopoietic. Integrated genomic and transcriptomic analyses reveal that Thr748 phosphorylation modulates Stat1 DNA binding, directly activating the Itgb4 promoter and enhancing integrin β4 expression in IECs following inflamamtion. In vitro intestinal organoid models, combined with gain- and loss-of-function experiments, show that Stat1 promotes integrin β4 expression via Thr748 phosphorylation following damage, boosting epithelial resilience independently of IFN-induced Tyrosine 701 (Tyr701) phosphorylation. In contrast, IFN stimulation triggers Tyr701 phosphorylation of Stat1, upregulating Zbp1—a sensor of cytotoxic damage-associated nucleic acids—while suppressing integrin β4, leading to epithelial cytotoxicity, which is mitigated by Thr748 phosphorylation. Our findings uncover a modular architecture of Stat1 signaling that enables epithelial adaptation to damage, with Thr748 phosphorylation acting as a rheostat to preserve tissue integrity while restricting IFN-mediated cytotoxicity.
2025-07-09 | GSE297455 | GEO
Project description:We identify arachidonic acid (AA), as a direct proliferation promoter of intestinal epithelial cells, facilitating small intestinal regeneration. In the transcriptomes, it shows that AA treatment upregulated proliferation-related genes including Wnt signaling target genes, while downregulated differentiation-related genes including enterocyte, goblet cell, Paneth cell, enteroendocrine cell, and tuft cell markers. Additionally, AA could also upregulate stem cell-associated genes which have been highly expressed three days after 12Gy IR injury (e.g. Clu, Lamc2, Anxa1, Areg, and Ly6d). The study shows that AA treatment can be considered a potential therapy for irradiation injury repair and tissue regeneration.
2020-07-27 | GSE146871 | GEO