Resolution of liver fibrosis requires myeloid cell–driven sinusoidal angiogenesis

Kantari‐Mimoun, Chahrazade; Castells, Magali; Klose, Ralph; Meinecke, Anna‐Katharina; Lemberger, Ursula; Rautou, Pierre‐Emmanuel; Pinot‐Roussel, Hélène; Badoual, Cécile; Schrödter, Katrin; Österreicher, Christoph H.; Fandrey, Joachim; Stockmann, Christian

doi:10.1002/hep.27635

Cited by 84 publications

(91 citation statements)

References 49 publications

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“…While monocyte-promoted angiogenesis is regularly observed in progressing fibrosis [19] , VEGF-stimulated sinusoidal angiogenesis might be a mandatory requirement for optimal fibrosis regression. This assumption is underpinned by the finding that both the genetic ablation of VEGF and the pharmacological inhibition of VEGF receptor 2 signaling prevent the angiogenic response and the resolution of liver fibrosis [20] . In line with these findings, VEGF neutralizing antibodies were able to prevent development of hepatic fibrosis but also disrupted fibrosis resolution in mice that were subjected to bile duct ligation [35] .…”

Section: Shifting the Hepatic Microenvironment From Inflammation To Rmentioning

confidence: 99%

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Liver Fibrosis: From Pathogenesis to Novel Therapies

Weiskirchen

Tacke²

2016

Dig Dis

131

100

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Chronic liver injury is accompanied by a dysbalanced scarring process, termed fibrosis. This process is mainly driven by chronic inflammation and an altered activity of a multitude of different chemokines and cytokines, resulting in the infiltration by immune cells (especially macrophages) and increase of matrix-expressing cell types. These processes might lead to cirrhosis representing the end-stage of fibrosis. Recent clinical studies comprising patients successfully treated for viral hepatitis showed that liver fibrogenesis and even cirrhosis may be reverted. The hepatic capacity to remodel scar tissue and to revert into a normal liver follows specific mechanistic principles that include the termination of chronic tissue damage, shifting the cellular bias from inflammation to resolution, initiation of myofibroblast apoptosis or senescence and, finally, fibrinolysis of excess scar tissue. The plurality of molecular and cellular triggers involved in initiation, progression and resolution of hepatic fibrogenesis offers an infinite number of therapeutic possibilities. For instance, inflammatory macrophages can be targeted via inhibition of chemokine CCL2 or its receptor CCR2 (e.g., by cenicriviroc) as well as by transfer of restorative macrophage subsets. Another target is galectin-3 that acts at various stages along the continuum from acute to chronic inflammation. Profibrogenic cytokines (e.g., transforming growth factor-β), matricellular proteins (e.g., CCN1/CYR61) or signaling pathways involved in fibrogenesis offer further possible targets. Other options are the application of therapeutic antibodies directed against components involved in biogenesis or remodeling of connective tissue such as lysyl oxidase-like-2 or synthetic bile acids like obeticholic acid that activate the farnesoid X receptor and was antifibrotic in a phase 2 study (FLINT trial). Factors affecting the gut barrier function or the intestinal microbiome further expanded the repertoire of drug targets. In this review, we discuss novel concepts in resolution of hepatic fibrosis and focus on drug targets that might be suitable to trigger resolution of fibrosis.

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Section: Shifting the Hepatic Microenvironment From Inflammation To Rmentioning

confidence: 99%

“…For details about TLR signaling refer to [12,13] . proteinases (MMP) thereby unmasking an unanticipated link between angiogenesis and the resolution of hepatic fibrosis [20] .…”

Section: Mechanisms Of Liver Fibrosis Regressionmentioning

confidence: 99%

Liver Fibrosis: From Pathogenesis to Novel Therapies

Weiskirchen

Tacke²

2016

Dig Dis

131

100

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“…Therefore, promoting angiogenesis can increase vascularity, and consequently decrease fibrogenic progression [27]. VEGF, a pro-angiogenic factor, is vital for the propagation and passage of endothelial cells and the formation of novel vascular networks [28].…”

Section: Discussionmentioning

confidence: 99%

Treatment Efficiency of Different Routes of Bone Marrow-Derived Mesenchymal Stem Cell Injection in Rat Liver Fibrosis Model

Idriss

Sayyed

Osama

et al. 2018

Cell Physiol Biochem

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Background/Aims: The most appropriate route for bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation in the management of liver fibrosis remains controversial. This study investigated the therapeutic efficacy of intravenous and intrasplenic BM-MSC transplantation on carbon tetrachloride (CCl₄)-induced rat liver fibrosis. Methods: Fifty rats were divided into 5 groups (n = 10 rats per group): healthy control group, CCl₄ group, CCl₄/ recovery group, CCl₄/BM-MSC intravenous group, and CCl₄/BM-MSC intrasplenic group. BM-MSCs were isolated, labeled with green fluorescent protein (GFP), and injected into fibrotic rats either intravenously or intrasplenically. Gene expression of interleukins (IL-1β and IL-6), interferon (INF)-γ, hepatic growth factor, and the hepatocyte-specific marker cytokeratin 18 was estimated by quantitative real-time reverse transcription-polymerase chain reaction. Vascular endothelial growth factor and connective tissue growth factor was detected by western blot analysis and enzyme-linked immunosorbent assay, respectively. At 2 weeks after intravenous and intrasplenic BM-MSC injections, GFP-positive cells were detected in liver tissue. Results: Both routes achieved a similar enhancement of liver function, which was confirmed by histopathological examination. The intravenous route was more effective than the intrasplenic route in reducing gene expression levels of IL-1β, IL-6, and INF-γ. However, fibrotic changes were still observed in the recovery group. Conclusion: Intravenous BM-MSC injection was an efficient and appropriate route for BM-MSC transplantation for the management of liver fibrosis.

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“…Genetic inactivation of VEGF in scar-infiltrating macrophages prevents the angio-genic response and abrogates fibrosis resolution in liver. 52) 6. CONCLUDING REMARKS Most relevant studies support the hypothesis that pathologic angiogenesis plays a critical role in liver fibrosis accompanied by chronic injury, persistent inflammation and progressive fibrogenesis.…”

Section: Angiogenesis-related Therapy For the Treatment Of Liver Fibrmentioning

confidence: 99%

Differential Roles of Angiogenesis in the Induction of Fibrogenesis and the Resolution of Fibrosis in Liver

Park

Kim

et al. 2015

Biological & Pharmaceutical Bulletin

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Liver fibrosis is a wound healing process that includes inflammation, deposition of extracellular matrix molecules, and pathological neovascularization. Angiogenesis, which is defined by the formation of new blood vessels from pre-existing vessels, is a complex and dynamic process under both physiological and pathological conditions. Although whether angiogenesis can induce or occur in parallel with the progression of hepatic fibrosis has not yet been determined, intrahepatic sinusoidal formation and remodeling are key features of liver fibrosis. Some recent evidence has suggested that experimental inhibition of angiogenesis ameliorates the development of liver fibrosis, while other recent studies indicate that neutralization or genetic ablation of vascular endothelial growth factor (VEGF) in myeloid cells can delay tissue repair and fibrosis resolution in damaged liver. In this review, we briefly summarize the current knowledge about the differential roles of angiogenesis in the induction of fibrogenesis and the resolution of fibrosis in damaged livers. Possible strategies for the prevention and treatment of liver fibrosis are also discussed.

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Resolution of liver fibrosis requires myeloid cell–driven sinusoidal angiogenesis

Cited by 84 publications

References 49 publications

Liver Fibrosis: From Pathogenesis to Novel Therapies

Liver Fibrosis: From Pathogenesis to Novel Therapies

Treatment Efficiency of Different Routes of Bone Marrow-Derived Mesenchymal Stem Cell Injection in Rat Liver Fibrosis Model

Differential Roles of Angiogenesis in the Induction of Fibrogenesis and the Resolution of Fibrosis in Liver

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