Abstract Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells representing the interface between blood cells on the one side and hepatocytes and hepatic stellate cells ...on the other side. LSECs represent a permeable barrier. Indeed, the association of fenestrae , absence of diaphragm and lack of basement membrane make them the most permeable endothelial cells of the mammalian body. They also have the highest endocytosis capacity of human cells. In physiological conditions, LSECs regulate hepatic vascular tone contributing to the maintenance of a low portal pressure despite the major changes in hepatic blood flow occurring during digestion. LSECs maintain hepatic stellate cell quiescence, thus inhibiting intrahepatic vasoconstriction and fibrosis development. In pathological conditions, LSECs play a key role in the initiation and progression of chronic liver diseases. Indeed, they become capillarized and lose their protective properties, and they promote angiogenesis and vasoconstriction. LSECs are implicated in liver regeneration following acute liver injury or partial hepatectomy since they renew from LSECs and/or LSEC progenitors, they sense changes in shear stress resulting from surgery, and they interact with platelets and inflammatory cells. LSECs also play a role in hepatocellular carcinoma development and progression, in aging, and in liver lesions related to inflammation and infection. This review also presents a detailed analysis of the technical aspects relevant for LSEC analysis including the markers these cells express, the available cell lines and the transgenic mouse models. Finally, this review provides an overview of the strategies available for a specific targeting of LSECs.
Chronic liver diseases with different etiologies represent a major public health issue worldwide. Liver fibrosis is the common feature of almost all chronic liver diseases and remains a key ...determinant of clinical prognosis. Over the last two decades, basic science studies have uncovered molecular mechanisms underlying the pathophysiology of chronic liver diseases, leading to the recent development of new anti-fibrotic drugs. These new drugs target different steps in the pathophysiology of chronic liver injury: metabolism of glucose, lipids and bile acids, apoptosis, inflammation and fibrosis. Many targets are shared between non-alcoholic steatohepatitis (NASH) and cholestatic diseases, explaining why some drugs have been assessed concurrently in both conditions. This review reports the most recent clinical trials designed to treat liver fibrosis, with a special focus on NASH and cholestatic diseases.
Magnetic resonance imaging (MRI) with magnetic resonance cholangiography (MRC) has become the radiologic standard of reference for diagnosis of primary sclerosing cholangitis (PSC). However, natural ...history of radiologic features of PSC is poorly known. In the current study, we aimed at analyzing the course of PSC using three‐dimensional (3D) MRC and liver MRI to find predictive radiologic features of progression. PSC patients, followed up in our center, with at least two 3D MRCs performed in at least a 1‐year interval, were retrospectively reviewed. We built an interpretation standard model to score precisely bile ducts and liver parenchyma features. The primary endpoint was overall radiologic course, including worsening, improvement, or stabilization. Radiologic features were analyzed by logistic regression. We reviewed 289 MRIs from 64 patients upon a mean radiologic follow‐up of 4 years (range, 1‐9). Radiologic features worsened in 37 patients (58%) and stabilized in 27 (42%); no patient showed improvement. Multivariate analysis resulted in two MRI progression risk scores, based on the combination of predictive radiologic features (score without gadolinium administration = 1 × dilatation of intrahepatic bile ducts + 2 × dysmorphy + 1 × portal hypertension; score with gadolinium administration = 1 × dysmorphy + 1 × parenchymal enhancement heterogeneity). These scores were associated with radiologic progression, with an area under the curve of 80 and 83% ± 4%. Conclusion: A majority of PSC patients develop radiologic aggravation upon MRI over 4 years. Two simple scores can predict radiologic progression.(Hepatology 2014;58:242–250)
Origins and functions of liver myofibroblasts Lemoinne, Sara; Cadoret, Axelle; El Mourabit, Haquima ...
Biochimica et biophysica acta,
07/2013, Letnik:
1832, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Myofibroblasts combine the matrix-producing functions of fibroblasts and the contractile properties of smooth muscle cells. They are the main effectors of fibrosis in all tissues and make a major ...contribution to other aspects of the wound healing response, including regeneration and angiogenesis. They display the de novo expression of α-smooth muscle actin. Myofibroblasts, which are absent from the normal liver, are derived from two major sources: hepatic stellate cells (HSCs) and portal mesenchymal cells in the injured liver. Reliable markers for distinguishing between the two subpopulations at the myofibroblast stage are currently lacking, but there is evidence to suggest that both myofibroblast cell types, each exposed to a particular microenvironment (e.g. hypoxia for HSC-MFs, ductular reaction for portal mesenchymal cell-derived myofibroblasts (PMFs)), expand and exert specialist functions, in scarring and inflammation for PMFs, and in vasoregulation and hepatocellular healing for HSC-MFs. Angiogenesis is a major mechanism by which myofibroblasts contribute to the progression of fibrosis in liver disease. It has been clearly demonstrated that liver fibrosis can regress, and this process involves a deactivation of myofibroblasts, although probably not to a fully quiescent phenotype. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
•Myofibroblasts are the main effectors of fibrosis in all tissues.•They also contribute to regeneration and angiogenesis.•They originate from resident fibroblasts and other cell types.•Liver myofibroblasts are derived from hepatic stellate cells and portal fibroblasts.•These two populations of myofibroblasts are thought to exert specialized functions.
Liver fibrosis expanding from portal tracts and vascular remodeling are determinant factors in the progression of liver diseases to cirrhosis. In the present study, we examined the potential ...contribution of portal myofibroblasts (PMFs) to the vascular changes leading to cirrhosis. The analyses of liver cells based on the transcriptome of rat PMFs, compared to hepatic stellate cell HSC‐derived myofibroblasts in culture, identified collagen, type XV, alpha 1 (COL15A1) as a marker of PMFs. Normal liver contained rare COL15A1‐immunoreactive cells adjacent to the bile ducts and canals of Hering in the portal area. A marked increase in COL15A1 expression occurred together with that of the endothelial marker, von Willebrand factor, in human and rat liver tissue, at advanced stages of fibrosis caused by either biliary or hepatocellular injury. In cirrhotic liver, COL15A1‐expressing PMFs adopted a perivascular distribution outlining vascular capillaries proximal to reactive ductules, within large fibrotic septa. The effect of PMFs on endothelial cells (ECs) was evaluated by in vitro and in vivo angiogenesis assays. PMF‐conditioned medium increased the migration and tubulogenesis of liver ECs as well as human umbilical vein ECs and triggered angiogenesis within Matrigel plugs in mice. In coculture, PMFs developed intercellular junctions with ECs and enhanced the formation of vascular structures. PMFs released vascular endothelial growth factor (VEGF)A‐containing microparticles, which activated VEGF receptor 2 in ECs and largely mediated their proangiogenic effect. Cholangiocytes potentiated the angiogenic properties of PMFs by increasing VEGFA expression and microparticle shedding in these cells. Conclusion: PMFs are key cells in hepatic vascular remodeling. They signal to ECs through VEGFA‐laden microparticles and act as mural cells for newly formed vessels, driving scar progression from portal tracts into the parenchyma. (Hepatology 2015;61:1041–1055)
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis ...is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is triggered by hypoxia and inflammation and is driven by the action of proangiogenic cytokines, mainly vascular endothelial growth factor (VEGF). In this review, we focus on liver angiogenesis associated with NAFLD and analyze the evidence of liver angiogenesis in animal models of NAFLD and in NAFLD patients. We also report the data explaining the role of angiogenesis in the progression of NAFLD and discuss the potential of targeting angiogenesis, notably VEGF, to treat NAFLD.
People with primary sclerosing cholangitis (PSC) have a variable and often progressive disease course that is associated with biliary and parenchymal changes. These changes are typically assessed by ...magnetic resonance imaging (MRI), including qualitative assessment of magnetic resonance cholangiopancreatography (MRCP). Our aim was to study the association of novel objective quantitative MRCP metrics with prognostic scores and patient outcomes.
We performed a retrospective study including 77 individuals with large-duct PSC with baseline MRCP images, which were postprocessed to obtain quantitative measures of bile ducts using MRCP+™. The participants’ ANALI scores, liver stiffness by vibration-controlled transient elastography, and biochemical indices were collected at baseline. Adverse outcome-free survival was measured as the absence of decompensated cirrhosis, liver transplantation (LT), or liver-related death over a 12-year period. The prognostic value of MRCP+-derived metrics was assessed by Cox regression modelling.
During a total of 386 patients-years, 16 cases of decompensation, 2 LTs, and 5 liver-related deaths were recorded. At baseline, around 50% of the patients were classified as being at risk of developing disease complications. MRCP+ metrics, particularly those describing the severity of bile duct dilatations, were correlated with all prognostic factors. Univariate analysis showed that MRCP+ metrics representing duct diameter, dilatations, and the percentage of ducts with strictures and/or dilatations were associated with survival. In a multivariable-adjusted analysis, the median duct diameter was significantly associated with survival (hazard ratio 10.9, 95% CI 1.3–90.3).
MRCP+ metrics in people with PSC correlate with biochemical, elastographic, and radiological prognostic scores and are predictive of adverse outcome-free survival.
In this study, we assessed in people with primary sclerosing cholangitis (PSC) the association of novel objective quantitative MRCP metrics automatically provided by a software tool (MRCP+) with prognostic scores and patient outcomes. We observed that MRCP+ metrics in people with PSC correlate with biochemical, elastographic, and radiological prognostic scores and are predictive of adverse outcome-free survival.
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•The association of quantitative MRCP+ biliary metrics with PSC severity and prognosis is still unknown.•MRCP+ biliary metrics in PSC are correlated with prognostic factors (LSM, Mayo score, AOM, and MRI scores).•MRCP+ biliary metrics are independently associated with prognosis in PSC.
Gallbladder enlargement is common in patients with primary sclerosing cholangitis (PSC). The gallbladder may confer hepatoprotection against bile acid overload, through the sequestration and ...cholecystohepatic shunt of bile acids. The aim of this study was to assess the potential impact of the gallbladder on disease features and bile acid homeostasis in PSC.
Patients with PSC from a single tertiary center who underwent liver MRI with three-dimensional cholangiography and concomitant analyses of serum bile acids were included. Gallbladder volume was measured by MRI and a cut-off of 50 ml was used to define gallbladder enlargement. Bile acid profiles and PSC severity, as assessed by blood tests and MRI features, were compared among patients according to gallbladder size (enlarged vs. normal-sized) or presence (removed vs. conserved). The impact of cholecystectomy was also assessed in the Abcb4 knockout mouse model of PSC.
Sixty-one patients with PSC, all treated with ursodeoxycholic acid (UDCA), were included. The gallbladder was enlarged in 30 patients, whereas 11 patients had been previously cholecystectomized. Patients with enlarged gallbladders had significantly lower alkaline phosphatase, a lower tauro-vs. glycoconjugate ratio and a higher UDCA vs. total bile acid ratio compared to those with normal-sized gallbladders. In addition, gallbladder volume negatively correlated with the hydrophobicity index of bile acids. Cholecystectomized patients displayed significantly higher aspartate aminotransferase and more severe bile duct strictures and dilatations compared to those with conserved gallbladder. In the Abcb4 knockout mice, cholecystectomy caused an increase in hepatic bile acid content and in circulating secondary bile acids, and an aggravation in cholangitis, inflammation and liver fibrosis.
Altogether, our findings indicate that the gallbladder fulfills protective functions in PSC.
In patients with primary sclerosing cholangitis (PSC), gallbladder status impacts on bile acid homeostasis and disease features. We found evidence of lessened bile acid toxicity in patients with PSC and enlarged gallbladders and of increased disease severity in those who were previously cholecystectomized. In the Abcb4 knockout mouse model of PSC, cholecystectomy causes an aggravation of cholangitis and liver fibrosis. Overall, our results suggest that the gallbladder plays a protective role in PSC.
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•Gallbladder enlargement is associated with alleviated cholestasis in patients with PSC.•Gallbladder volume is negatively correlated with bile acid hydrophobicity in PSC.•Cholecystectomized patients with PSC display more severe cholangiographic features.•Cholecystectomy aggravates cholangitis and liver fibrosis in Abcb4 knockout mice.
The low-phospholipid-associated cholelithiasis (LPAC) syndrome is a recently described peculiar form of cholelithiasis associated with the ATP-binding-cassette subfamily B, member 4 (ABCB4) gene ...deficiency. The purpose of our study was to analyse the relationship between magnetic resonance (MR) features and the genetic status of ABCB4 in people with LPAC syndrome.
A total of 233 individuals with proven LPAC syndrome were enrolled between January 2003 and June 2018 in a retrospective single-centre study. Inclusion criteria included availability of clinical files, MR images, and genetic data. MR images were analysed by consensus among 3 senior radiologists blinded to the status of ABCB4 gene mutation.
A total of 125 individuals (mean age at first MR imaging 40.8 years; 66% females; 48% ABCB4 variant) were included. MR abnormalities were found in 61 (49%) of the 125 individuals. Forty (67%) of the 60 individuals with an ABCB4 gene variant had MR abnormalities as compared with 21 (33%) of the 65 individuals without an ABCB4 gene variant (odds ratio OR 4.1, 95% CI 1.9–9.5, p = 0.0001). Compared to individuals with no variant, individuals with an ABCB4 variant were more likely to show intrahepatic macrolithiasis (56 vs. 17%; OR 6.3, 95% CI 2.6–16.2, p <0.0001), bile duct dilatation (60 vs. 18%; OR 6.5, 95% CI 2.7–16.3, p <0.0001), and at least 1 MR feature of complication (35 vs. 15%; OR 2.9, 95% CI 1.1–7.8, p <0.05).
ABCB4-related LPAC syndrome is associated with more frequent and severe hepatobiliary MR abnormalities. This finding strongly supports the major role of the ABCB4 gene in the pathogenesis of LPAC syndrome and highlights a genotype–phenotype association in this inherited disease with genetic heterogeneity.
ABCB4-related LPAC syndrome associated with an ABCB4 gene variant demonstrates more frequent and severe hepatobiliary MR abnormalities. This finding supports the major role of the ABCB4 gene in the pathogenesis of LPAC syndrome.
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•We analysed the relationship between MRI and the genetic status of ABCB4 in LPAC.•MR abnormalities were found in 61 (49%) of the 125 individuals with LPAC syndrome.•Forty (67%) of the 60 individuals with an ABCB4 gene variant had MR abnormalities.•Twenty-one (33%) of the 65 individuals without an ABCB4 gene variant had MR abnormalities.•ABCB4-related LPAC is associated with more frequent and severe MR abnormalities.
Liver fibrogenesis is a dynamic process including quantitative and qualitative changes of the extracellular matrix, of which the most prominent is the deposition of type I collagen. These changes ...progressively disrupt normal liver architecture and result in cirrhosis formation. In the fibrotic liver, as in all other fibrotic tissues, the extracellular matrix is produced by cells usually characterized by the de novo expression of alpha-smooth muscle actin and known as myofibroblasts. Portal myofibroblasts (PMFs) appear to be critical in pathological angiogenesis, which constantly occurs in advanced liver fibrosis. Whereas the association between angiogenesis and fibrosis during the progression of liver diseases remains to be elucidated, we suggest that collagen-type-XV-alpha1-producing PMFs could provide an important link both by stabilizing newly formed vessels and by forming a scaffold for the deposition of interstitial collagen.
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