Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(14), С. 7873 - 7873

Опубликована: Июль 18, 2024

The burden of chronic liver disease is globally increasing at an alarming rate. Chronic injury leads to inflammation and fibrosis (LF) as critical determinants long-term outcomes such cirrhosis, cancer, mortality. LF a wound-healing process characterized by excessive deposition extracellular matrix (ECM) proteins due the activation hepatic stellate cells (HSCs). In healthy liver, quiescent HSCs metabolize store retinoids. Upon fibrogenic activation, transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; produce proinflammatory soluble mediators, collagens, inhibitors ECM degradation. Activated are main effector during fibrogenesis. addition, accumulation profibrogenic macrophages in response hepatocyte death play role initiation HSC survival. source myofibroblasts resident HSCs. migrate site active fibrogenesis initiate formation fibrous scar. Single-cell technologies revealed that highly homogenous, while activated HSCs/myofibroblasts much more heterogeneous. complex results from various hepatocellular inflammatory signals related intrahepatic pathways or extrahepatic mediators. Inflammatory processes modulate activating and, turn, drive immune mechanisms via cytokines chemokines. Increasing evidence also suggests cellular stress responses contribute Recent data demonstrated can revert even advanced stages cirrhosis if underlying cause eliminated, which inhibits cells. However, despite numerous clinical studies on plausible drug candidates, approved antifibrotic therapy still remains elusive. This state-of-the-art review presents molecular involved its resolution, well comprehensively discusses drivers linking LF.

Язык: Английский

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Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

Metabolites, Год журнала: 2024, Номер 14(1), С. 40 - 40

Опубликована: Янв. 8, 2024

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated (MASH), is a systemic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed identify effective pharmacological treatments and, therefore, lifestyle changes are cornerstone of therapy for NASH. with this context, we analyze epidemiological burden possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming metabolism, hypoxia, all which eventually culminate in low-grade chronic inflammation increased risk fibrosis progression. The explanations underlying failure also accurately examined. We conclude high heterogeneity NASH, resulting from variable backgrounds, exposure, responses different stresses, susceptibility hepatocyte differences repair-response, calls personalized medicine approaches involving research on noninvasive biomarkers. Future should aim at achieving complete assessment determinants, modifiers, correlates thus adopting more holistic unbiased approach, notably including cardiovascular–kidney–metabolic outcomes, without restricting therapeutic perspectives histological surrogates liver-related outcomes alone.

Язык: Английский

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Lipid-associated macrophages’ promotion of fibrosis resolution during MASH regression requires TREM2

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(35)

Опубликована: Авг. 22, 2024

While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages MASH regression is poorly understood. Comparing progression vs regression, we identified specific subpopulations that are critical for MASH/fibrosis resolution. We elucidated restorative pathways and gene signatures define regression-associated establish importance TREM2 + regression. Liver-resident Kupffer cells lost replaced by four distinct monocyte-derived subpopulations. Trem2 expressed in two subpopulations: i) occupying cell niche (MoKC) ii) lipid-associated (LAM). In livers, no new transcriptionally subpopulation emerged. However, relative composition changed compared to MASH. MoKC was major MASH, they decreased LAM dominant subtype maintained expression. Both were enriched disease-resolving pathways. Absence restricted emergence LAMs formation hepatic crown-like structures. functionally important not only restricting MASH-fibrosis but also effective inflammation fibrosis. superior collagen degraders. Lack prevented elimination steatosis inactivation HSC indicating their significance coordination with other types liver. imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, degradation.

Язык: Английский

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Role of gut microbiota and immune cells in metabolic-associated fatty liver disease: clinical impact

Hepatology International, Год журнала: 2024, Номер 18(S2), С. 861 - 872

Опубликована: Июль 12, 2024

Язык: Английский

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Single-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesis

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 16, 2025

Chronic liver diseases are highly linked with mitochondrial dysfunction and macrophage infiltration. Mallory-Denk bodies (MDBs) protein aggregates associated hepatic inflammation, MDBs pathogenesis could be induced in mice by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Here, we investigate the heterogeneity role of during on DDC-induced mouse model single-nucleus RNA sequencing (snRNA-seq). We defined macrophages into four distinct subsets including monocyte-derived (MDMs) subset three Kupffer cells (KCs) (Gpnmbhigh KCs, Peam1high Gpnmblow Pecam1low KCs). Particularly, identified a novel Gpnmbhigh KCs as lipid-associated (LAM) high expression Trem2, CD63, CD9. Interestingly, LAM showed potential immunosuppressive characteristic expressing anti-inflammatory genes IL-7R formation. Using contact transwell co-culture systems, released mtDNA from hepatocytes was found to induce activation inflammasome macrophages. Furthermore, revealed damaged DNA activate NOD-like receptor family pyrin domain containing-3 (NLRP3) subsequently form apoptosis-associated speck-like containing caspase recruit (ASC) specks Collectively, our results firstly injured pathogenesis, providing crucial understanding chronic disease.

Язык: Английский

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Immune Checkpoints and the Immunology of Liver Fibrosis

Livers, Год журнала: 2025, Номер 5(1), С. 5 - 5

Опубликована: Янв. 27, 2025

Liver fibrosis is a very complicated dynamic process where several immune cells are involved. Both innate and adaptive immunity implicated, their interplay always present. Multi-directional interactions between liver macrophages, hepatic stellate (HSCs), cells, cytokines important for the induction perpetuation of fibrosis. Detailed studies proteomics transcriptomics have produced new evidence role individual in cirrhosis. Most these controlled by various checkpoints whose main function to maintain homeostasis implicated cells. Recent indicates that involved In particular, programmed cell death protein 1 (PD-1), death-ligand (PD-L1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) been investigated, particularly after availability checkpoint inhibitors. Their activation leads exhaustion CD4+ve CD8+ve promotion this review, current pathogenesis immunological abnormalities discussed. The recent data on involvement identified as possible targets future interventions.

Язык: Английский

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Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Март 7, 2025

Abstract Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in defense, surveillance, and homeostasis. This review systematically discusses types of hematopoietic progenitors that give rise macrophages, including primitive progenitors, erythro-myeloid stem cells. These have distinct genetic backgrounds developmental processes. Accordingly, macrophages exhibit complex diverse functions body, phagocytosis clearance cellular debris, antigen presentation, response, regulation inflammation cytokine production, tissue remodeling repair, multi-level regulatory signaling pathways/crosstalk involved homeostasis physiology. Besides, tumor-associated a key component TME, exhibiting both anti-tumor pro-tumor properties. Furthermore, functional status is closely linked development various diseases, cancer, autoimmune disorders, cardiovascular disease, neurodegenerative metabolic conditions, trauma. Targeting has emerged as promising therapeutic strategy these contexts. Clinical trials macrophage-based targeted drugs, immunotherapies, nanoparticle-based therapy were comprehensively summarized. Potential challenges future directions targeting also been discussed. Overall, our highlights significance this versatile cell human health which expected inform research clinical practice.

Язык: Английский

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Macrophages and platelets in liver fibrosis and hepatocellular carcinoma

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Дек. 5, 2023

During fibrosis, (myo)fibroblasts deposit large amounts of extracellular matrix proteins, thereby replacing healthy functional tissue. In liver this leads to the loss hepatocyte function, portal hypertension, variceal bleeding, and increased susceptibility infection. At an early stage, fibrosis is a dynamic reversible process, however, from cirrhotic there significant progression hepatocellular carcinoma. Both liver-resident macrophages (Kupffer cells) monocyte-derived are important drivers progression, but can also induce its regression once triggers chronic inflammation eliminated. cancer, they attracted tumor site become tumor-associated (TAMs) polarized towards M2- anti-inflammatory/tumor-promoting phenotype. Besides their role in thrombosis hemostasis, platelets stimulate development by secreting profibrogenic factors regulating innate immune response, e.g., interacting with monocytes macrophages. Here, we review recent literature on interplay

Язык: Английский

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Dried tangerine peel polysaccharide (DTPP) alleviates hepatic steatosis by suppressing TLR4/MD-2-mediated inflammation and endoplasmic reticulum stress

Bioorganic Chemistry, Год журнала: 2024, Номер 147, С. 107369 - 107369

Опубликована: Апрель 16, 2024

Язык: Английский

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Altered lipid metabolism as a predisposing factor for liver metastasis in MASLD

Molecules and Cells, Год журнала: 2024, Номер 47(2), С. 100010 - 100010

Опубликована: Янв. 21, 2024

Recently, the incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing due to high prevalence conditions, such as obesity and type 2 diabetes mellitus. Steatotic a hotspot for cancer metastasis in MASLD. Altered lipid metabolism, hallmark MASLD, remodels tissue microenvironment, making it conducive growth metastatic cancer. Tumors exacerbate dysregulation hepatic metabolism by releasing extracellular vesicles particles into liver. influences proliferation, differentiation, functions immune cells, contributing formation an immunosuppressive metastasis-prone microenvironment This review discusses mechanisms which promotes progression, focusing on its role fostering Furthermore, this highlights manipulation strategies therapeutic management

Язык: Английский

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