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Macrophages trigger injury-induced hepatocyte reprogramming via IL-6/gp130/STAT3 axis [RNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE193849 | GEO | 2022/08/24

REPOSITORIES: GEO

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Macrophages trigger injury-induced hepatocyte reprogramming via IL-6/gp130/STAT3 axis [ChIP-Seq]

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

Hepatocyte SREBP signaling mediates clock communication within the liver [ATAC-seq]

Project description:Rhythmic intraorgan communication coordinates environmental signals and cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific knockout of core components of the molecular clock, Rev-erba and b (ReverbhDKO), alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in non-parenchymal cells (NPC) of the liver. Here we report that in diet induced obesity (DIO)-caused fatty liver, hepatocyte SREBP cleavage-activating protein (SCAP) is required for ReverbhDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in Kupffer cells (KC). Integrative analyses of isolated hepatocytes and Kupffer cells uncovered potential signals, including secreted polypeptides and metabolites, that gain rhythmicity in the absence of REV-ERBs in a SCAP-dependent manner. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in DIO and fatty liver disease.

2023-04-04 | GSE206318 | GEO

Hepatocyte SREBP signaling mediates clock communication within the liver [scRNA-seq]

2023-04-04 | GSE206317 | GEO

Hepatocyte SREBP signaling mediates clock communication within the liver [RNA-seq]

2023-04-04 | GSE206316 | GEO

A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver injury-associated YAP signaling (ChIP-seq)

Project description:Following injury, differentiated epithelial cells can serve as a stem cell-independent source for tissue regeneration by undergoing reprogramming into other cell types. The intrinsic molecular basis underlying plasticity of differentiated cells remains largely unaddressed. Here we show that Arid1a, a key component of the SWI/SNF chromatin remodeling complex, controls liver regeneration and gene expression associated with emergence of injury-induced progenitor-like cells (LPLCs). Hepatocyte-specific Arid1a ablation reduces LPLC gene expression in several models of periportal liver injury and impairs liver regeneration, leading to organ dysfunction. Arid1a establishes a permissive chromatin state at LPLC-enriched genes during homeostasis, suggesting it endows hepatocytes with competence to respond to injury-induced signals. Consistently, Arid1a facilitates binding of YAP, a critical regeneration signaling pathway, to LPLC-enriched genes, and Arid1a deletion prevents their YAP-associated induction following injury. Together, these findings provide a framework for studying the contributions of injury-induced LPLCs to periportal liver regeneration.

2019-07-07 | GSE111500 | GEO

A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver injury-associated YAP signaling (ATAC-seq)

2019-07-07 | GSE111499 | GEO

A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver injury-associated YAP signaling (RNA-seq)

2019-07-07 | GSE111501 | GEO

PR-SET7 inactivation causes hepatocyte necrosis and spontaneous development of hepatocellular carcinoma derived from ductal progenitor cells

Project description:PR-SET7-mediated histone-4 lysine-20 methylation has been implicated in mitotic condensation, DNA damage response and replication licencing. Here we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis with unusual features of autophagy, termed "endonucleosis". Necrotic death was accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells. Prolonged necrotic-regenerative cycles coupled with oncogenic STAT3 activation replaced pre-existing hepatocytes with hepatocellular carcinoma derived entirely from ductal progenitor cells. Hepatocellular carcinoma in these mice displays a cancer stem cell gene signature specified by the co-expression of ductal progenitor markers and oncofetal genes. Mice carrying hepatocyte specific inactivation of PR-SET7 were generated in order to investigate the function of PR-SET7 histone methyl transferase in liver organogenesis, hepatocyte proliferation and liver regeneration. P15 WT mice were injected intra-peritoneally (ip) with 25ml per kg DEN (diethyl nitrosamine). Mice were examined for RNA expression at 8 months old.

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A New Liver-Regeneration Molecular Mechanism Involving Hepatic Stellate Cells, Kupffer Cells, and Glucose-Regulated Protein 78 as a New Hepatotrophic Factor

Project description:Background and aims: Lethal liver failure is an important clinical issue. To overcome liver failure, we focused on liver regeneration mechanisms by activation of HSCs and KCs. It is known that the HSC-secreted Mac-2 binding protein glycan isomer (M2BPGi) has a function to activate Kupffer cells (KCs) in fibrotic liver. However, the importance and functional mechanism of liver regeneration by HSCs/M2BPGi/KCs axis in remnant liver after hepatectomy are still unknown. The aim of this study is to clarify whether the HSCs-derived M2BPGi can activate KCs in damaged-liver by not only fibrosis but also after hepatectomy and to elucidate the new molecular mechanism of liver regeneration by HSCs and KCs. Methods: We examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi-activated KCs by proteomics approach. Further, the effect of Glucose-regulated protein 78 (GRP78) as one of the M2BPGi-related secreted proteins on liver regeneration was examined in in vitro analysis and mouse hepatectomy model. Results: Although M2BPGi had no hepatocyte promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KCs-drived GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration in 70% hepatectomy mice and increased the survival rate in lethal 90% hepatectomy mice with liver failure. Conclusion: The M2BPGi activated-KCs extract the GRP78 which facilitates liver regeneration via activation of the proliferation potency of hepatocytes. Moreover, GRP78 administration could improve the survival in the lethal mice model. Our data suggested that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure in the clinic.

2021-06-29 | GSE179005 | GEO

CINC-2 and miR-199a-5p in exosomes secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration

Project description:Small hepatocyte-like progenitor cells (SHPCs) are hepatocytic progenitor cells that transiently form clusters in rat livers treated with retrorsine and with 70% partial hepatectomy (PH). We previously reported that transplantation of Thy1+ cells derived from D-galactosamine-treated livers promotes SHPC expansion, resulting in the acceleration of liver regeneration. Extracellular vesicles (EVs) produced by Thy1+ cells act on sinusoidal endothelial cells (SECs) and Kupffer cells to secrete IL17B and IL25, respectively, resulting in SHPC activation through IL17 receptor B (RB) signaling. Our aim is to identify factors in Thy1-EVs that activate IL17RB signaling. Thy1+ cells isolated from rats with D-galactosamine-induced liver injury were cultured for one week. Although some liver stem/progenitor cells proliferated into colonies, others maintained as mesenchymal cells (MCs). Thy1-MCs or Thy1-liver stem/progenitor cells were transplanted into retrorsine/PHtreated livers to examine their effects on SHPCs. SHs isolated from adult rat livers were used to validate factors regulating growth induction. The number and size of SHPCs remarkably increased in livers transplanted with Thy1-MCs. Comprehensive analysis of Thy1-MC-EVs revealed that miR-199a-5p, CINC-2, and MCP-1 are candidates for stimulating SHPC growth. Administration of the miR-199a-5p mimic, and not CINC-2, promoted SH growth. SECs treated with CINC-2 induced IL17b expression and their conditioned medium promoted SH growth. Thy1-MC transplantation may accelerate liver regeneration due to SHPCs expansion, which is stimulated by CINC-2/IL17RB signaling and miR-199a-5p.

2023-04-07 | PXD039384 | Pride

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