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Project description:The liver is a pivotal organ possessing remarkable regenerative capacity. By employing murine liver injury models and lineage tracing strategy, recent studies have demonstrated that differentiated hepatocytes undergo reprogramming to SOX9+HNF4α+ liver progenitor-like cells (LPLCs), and serve as a totally new cell source for mammalian liver regeneration. However, it is largely unknown how hepatocyte reprogramming is regulated. In this study, we focus on analyzing the microenvironment cues in triggering hepatocyte reprogramming in liver injuries. By performing single-cell RNA sequencing (scRNA-seq) of hepatocyte reprogramming in liver injury, we find immune response is significantly activated. Notably, by lineage depletion, macrophages, especially kupffer cells, but not T cells, B cells, natural killer cells or neutrophils, are found essential for hepatocyte reprogramming and liver regeneration. IL-6, derived specifically from activated kupffer cells, triggers hepatocyte reprogramming via gp130/STAT3 signaling. Furthermore, STAT3 triggers gene expression by binding to Arid1a-dependent pre-opened regeneration-responsive enhancers (RREs) of reprogramming genes. Collectively, this study provides key insights into kupffer cells/IL-6/STAT3-mediated hepatocyte reprogramming and liver regeneration, which may serve as the base for new therapeutic strategies in facilitating endogenous repair mechanisms.
2022-08-24 | GSE193848 | GEO
Project description:The liver is a pivotal organ possessing remarkable regenerative capacity. By employing murine liver injury models and lineage tracing strategy, recent studies have demonstrated that differentiated hepatocytes undergo reprogramming to SOX9+HNF4α+ liver progenitor-like cells (LPLCs), and serve as a totally new cell source for mammalian liver regeneration. However, it is largely unknown how hepatocyte reprogramming is regulated. In this study, we focus on analyzing the microenvironment cues in triggering hepatocyte reprogramming in liver injuries. By performing single-cell RNA sequencing (scRNA-seq) of hepatocyte reprogramming in liver injury, we find immune response is significantly activated. Notably, by lineage depletion, macrophages, especially kupffer cells, but not T cells, B cells, natural killer cells or neutrophils, are found essential for hepatocyte reprogramming and liver regeneration. IL-6, derived specifically from activated kupffer cells, triggers hepatocyte reprogramming via gp130/STAT3 signaling. Furthermore, STAT3 triggers gene expression by binding to Arid1a-dependent pre-opened regeneration-responsive enhancers (RREs) of reprogramming genes. Collectively, this study provides key insights into kupffer cells/IL-6/STAT3-mediated hepatocyte reprogramming and liver regeneration, which may serve as the base for new therapeutic strategies in facilitating endogenous repair mechanisms.
2022-08-24 | GSE193849 | GEO
Project description:Macrophages trigger injury-induced hepatocyte reprogramming via IL-6/gp130/STAT3 axis
| PRJNA798082 | ENA
Project description:Macrophages trigger injury-induced hepatocyte reprogramming via IL-6/gp130/STAT3 axis [ChIP-Seq]
| PRJNA798086 | ENA
Project description:Macrophages trigger injury-induced hepatocyte reprogramming via IL-6/gp130/STAT3 axis [RNA-Seq]
| PRJNA798085 | ENA
Project description:AimTo investigate the effect of the gp130/STAT3-endoplasmic reticulum (ER) stress axis on hepatocyte necroptosis during acute liver injury.MethodsER stress and liver injury in LO2 cells were induced with thapsigargin, and in BALB/c mice with tunicamycin and carbon tetrachloride (CCl4). Glycoprotein 130 (gp130) expression, the degrees of ER stress, and hepatocyte necroptosis were assessed.ResultsER stress significantly upregulated gp130 expression in LO2 cells and mouse livers. The silencing of activating transcription factor 6 (ATF6), but not of ATF4, increased hepatocyte necroptosis and mitigated gp130 expression in LO2 cells and mice. Gp130 silencing reduced the phosphorylation of CCl4-induced signal transducer and activator of transcription 3 (STAT3), and aggravated ER stress, necroptosis, and liver injury in mice.ConclusionATF6/gp130/STAT3 signaling attenuates necroptosis in hepatocytes through the negative regulation of ER stress during liver injury. Hepatocyte ATF6/gp130/STAT3 signaling may be used as a therapeutic target in acute liver injury.
| S-EPMC10332293 | biostudies-literature
Project description:BackgroundPeriodontitis is a major oral condition and current treatment outcomes can be unsatisfactory. Macrophages are essential to the regeneration process, so we investigated the influence of human dental pulp stem cells (hDPSCs) on macrophage differentiation and the microenvironment and the underlying mechanism.MethodshDPSCs were isolated from healthy third molars extracted from patients undergoing maxillofacial surgery. The surface antigens CD73, CD45, CD90 and CD11b of the hDPSCs were detected using flow cytometry. hDPSCs were induced for osteogenic and adipogenic differentiation, and the outcome was assessed by alizarin red staining or Oil Red O staining. The IL-6 level released by hDPSCs was measured by enzyme linked immunosorbent assay (ELISA). Tohoku Hospital Pediatrics-1 (THP-1) cells were cultured and induced into macrophages by phorbol-12-myristate-13-acetate. After coculture of THP-1-derived macrophages with hDPSCs, interleukin 6 (IL-6), Argininase-1 (Arg-1), Mannose receptor C-1 (Mrc-1), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF-α) levels in the medium were measured using ELISA and quantificational RT-PCR (qRT-PCR). The numbers of CD80+ and CD163+ macrophages were counted by immunofluorescence, and GP130/STAT3 signaling protein expression was detected. After coculturing the culture medium of hDPSCs with human bone marrow stem cells (BMSCs), scratch assays and transwell assays were performed to evaluate cell migration and invasion.ResultsAlkaline phosphatase (ALP) staining, alizarin red staining, and western blots were performed to assess osteoblast differentiation. The hDPSCs were positive for surface antigens CD73 and CD90 and negative for CD45 and CD11b expression. The level of IL-6 secreted by hDPSCs significantly increased the number of CD80+ cells as well as the levels of Arg-1 and Mrc-1. It also promoted M2 macrophage polarization and activated GP130/STAT3 signaling. However, the medium cocultured with THP-1-derived macrophages by hDPSCs facilitated the migration, invasion, and osteogenic abilities of human bone marrow-derived stem cells (hBMSCs).ConclusionshDPSCs can regulate the periodontal microenvironment through IL-6 by inducing phenotypic transformation of M2 macrophages and stimulating osteogenic differentiation of BMSCs.
| S-EPMC9929758 | biostudies-literature
Project description:N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11/IL11RA/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKOIl11) or gp130 (CKOgp130) in adult hepatocytes. Following APAP, as compared to controls, CKOgp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKOgp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKOIl11 mice that, as compared to wild-type mice, had lower APAP-induced ALT/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKOgp130 mice, APAP-treated CKOIl11 mice had lesser ERK/JNK/NOX4 activation and greater features of regeneration. Both CKOgp130 and CKOIl11 mice had normal APAP metabolism. After APAP, CKOgp130 and CKOIl11 mice had reduced Il6, Ccl2, Ccl5, Il1β, and Tnfα expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative.
| S-EPMC9266364 | biostudies-literature
Project description:Resistance of tumor cells to chemoradiotherapy represents a fundamental problem in clinical oncology. The underlying mechanisms are actively debated. Here we show that blocking inflammatory cytokine receptor signaling via STAT3 re-sensitized treatment-refractory cancer cells and abolished tumor growth in a xenograft mouse model when applied together with chemoradiotherapy. STAT3 executed treatment resistance by triggering the expression of RBPJ, the key transcriptional regulator of the NOTCH pathway. The mandatory RBPJ interaction partner, NOTCH intracellular domain, was provided by tumor cell-intrinsic expression of NOTCH ligands that caused tonic NOTCH proteolysis. In fact, NOTCH inhibition phenocopied the effect of blocking STAT3 signaling. Moreover, genetic profiling of rectal cancer patients revealed the importance of the STAT3/NOTCH axis as NOTCH expression correlated with clinical outcome. Our data uncovered an unprecedented signal alliance between inflammation and cellular development that orchestrated resistance to chemoradiotherapy. Clinically, our findings allow for biomarker-driven patient stratification and offer novel treatment options.
| S-EPMC7865718 | biostudies-literature
Project description:Ischemia and reperfusion (I/R) injury following liver transplantation (LTx) is an important problem that significantly impacts clinical outcomes. IFN regulatory factor-1 (IRF-1) is a nuclear transcription factor that plays a critical role in liver injury. Our objective was to determine the immunomodulatory role of IRF-1 during I/R injury following allogeneic LTx. IRF-1 was induced in liver grafts immediately after reperfusion in both human and mouse LTx. IRF-1 contributed significantly to I/R injury because IRF-1-knockout (KO) grafts displayed much less damage as assessed by serum alanine aminotransferase and histology. In vitro, IRF-1 regulated both constitutive and induced expression of IL-15, as well as IL-15Rα mRNA expression in murine hepatocytes and liver dendritic cells. Specific knockdown of IRF-1 in human primary hepatocytes gave similar results. In addition, we identified hepatocytes as the major producer of soluble IL-15/IL-15Rα complexes in the liver. IRF-1-KO livers had significantly reduced NK, NKT, and CD8(+) T cell numbers, whereas rIL-15/IL-15Rα restored these immune cells, augmented cytotoxic effector molecules, promoted systemic inflammatory responses, and exacerbated liver injury in IRF-1-KO graft recipients. These results indicate that IRF-1 promotes LTx I/R injury via hepatocyte IL-15/IL-15Rα production and suggest that targeting IRF-1 and IL-15/IL-15Rα may be effective in reducing I/R injury associated with LTx.
| S-EPMC4458432 | biostudies-literature