Origins and functions of liver myofibroblasts

AbstractMyofibroblasts 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

Protective potential of the gallbladder in primary sclerosing cholangitis

Background & Aims: 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.Methods: 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.Results: 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.Conclusion: Altogether, our findings indicate that the gallbladder fulfills protective functions in PSC.Impact and implications: 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 gall-bladders 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.& COPY; 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Cold-Atmospheric Plasma Induces Tumor Cell Death in Preclinical In Vivo and In Vitro Models of Human Cholangiocarcinoma

Through the last decade, cold atmospheric plasma (CAP) has emerged as an innovative therapeutic option for cancer treatment. Recently, we have set up a potentially safe atmospheric pressure plasma jet device that displays antitumoral properties in a preclinical model of cholangiocarcinoma (CCA), a rare and very aggressive cancer emerging from the biliary tree with few efficient treatments. In the present study, we aimed at deciphering the molecular mechanisms underlying the antitumor effects of CAP towards CCA in both an in vivo and in vitro context. In vivo, using subcutaneous xenografts into immunocompromised mice, CAP treatment of CCA induced DNA lesions and tumor cell apoptosis, as evaluated by 8-oxoguanine and cleaved caspase-3 immunohistochemistry, respectively. The analysis of the tumor microenvironment showed changes in markers related to macrophage polarization. In vitro, the incubation of CCA cells with CAP-treated culture media (i.e., plasma-activated media, PAM) led to a dose response decrease in cell survival. At molecular level, CAP treatment induced double-strand DNA breaks, followed by an increased phosphorylation and activation of the cell cycle master regulators CHK1 and p53, leading to cell cycle arrest and cell death by apoptosis. In conclusion, CAP is a novel therapeutic option to consider for CCA in the future

Applicability and precautions of use of liver injury biomarker FibroTest. A reappraisal at 7 years of age

<p>Abstract</p> <p>Background</p> <p>FibroTest (FT) is a validated biomarker of fibrosis. To assess the applicability rate and to reduce the risk of false positives/negatives (RFPN), security algorithms were developed. The aims were to estimate the prevalence of RFPN and of proven failures, and to identify factors associated with their occurrences.</p> <p>Methods</p> <p>Four populations were studied: 954 blood donors (P1), 7,494 healthy volunteers (P2), 345,695 consecutive worldwide sera (P3), including 24,872 sera analyzed in a tertiary care centre (GHPS) (P4). Analytical procedures of laboratories with RFPN > 5% and charts of P4 patients in with RFPN were reviewed.</p> <p>Results</p> <p>The prevalence of RFPN was 0.52% (5/954; 95%CI 0.17-1.22) in P1, 0.51% (38/7494; 0.36-0.70) in P2, and 0.97% (3349/345695; 0.94-1.00) in P3. Three a priori high-risk populations were confirmed: 1.97% in P4, 1.77% in HIV centre and 2.61% in Sub-Saharan origin subjects. RFPN was mostly associated with low haptoglobin (0.46%), and high apolipoproteinA1 (0.21%). A traceability study of a P3 laboratory with RFPFN > 5% permitted to correct analytical procedures.</p> <p>Conclusion</p> <p>The mean applicability rate of Fibrotest was 99.03%. Independent factors associated with the high risk of false positives/negatives were HIV center, subSaharan origin, and a tertiary care reference centre, although the applicability rate remained above 97%.</p

Characterization of animal models for primary sclerosing cholangitis (PSC)

SummaryPrimary sclerosing cholangitis (PSC) is a chronic cholangiopathy characterized by biliary fibrosis, development of cholestasis and end stage liver disease, high risk of malignancy, and frequent need for liver transplantation. The poor understanding of its pathogenesis is also reflected in the lack of effective medical treatment. Well-characterized animal models are utterly needed to develop novel pathogenetic concepts and study new treatment strategies. Currently there is no consensus on how to evaluate and characterize potential PSC models, which makes direct comparison of experimental results and effective exchange of study material between research groups difficult. The International Primary Sclerosing Cholangitis Study Group (IPSCSG) has therefore summarized these key issues in a position paper proposing standard requirements for the study of animal models of PSC

Gallstone disease, towards a better understanding and clinical practice

International audienc

Le récepteur de l'EGF (médiateur de la surproduction de mucines et de l'inflammation dans l'épithélium biliaire. Implication dans la lithiase biliaire)

La lithiase biliaire, définie par la présence de calculs dans les voies biliaires, est un enjeu majeur de santé publique. Si la surproduction de mucines est un élément central de la lithogenèse biliaire, les mécanismes impliqués dans cette surproduction restent à identifier. Par une approche ex vivo et in vitro, notre travail a démontré que dans un contexte inflammatoire, l EGF-R, récepteur à activité tyrosine kinase, avait un rôle essentiel dans la surproduction de la mucine MUC5AC par les cellules épithéliales biliaires. Dans la seconde partie du travail, nous avons montré que, dans des cellules biliaires tumorales, le LPS active, une boucle positive de rétrocontrôle induisant l amplification de l activation de la voie de l EGF-R via la voie COX-2/PGE2. Cette amplification initiée par le LPS, présent dans la bile dans les pathologies biliaires inflammatoires, notamment lithiasiques, pourrait permettre de faire le lien entre l inflammation chronique et la carcinogenèse biliaire.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Anomalies hépatobiliaires associées à la mucoviscidose

Des anomalies hépatobiliaires sont observées chez 30 à 40% des patients atteints de mucoviscidose mais seuls 5 à 10% développent une cirrhose. Nous présentons des travaux expérimentaux réalisés principalement chez la souris invalidée pour le gène cftr de la lignée cftrtm1Unc. Chez ces souris de fond génétique mixte et traitées par polyéthylèneglycol, nous n avons pas constaté de lésions hépatobiliaires, mais un défaut d alcalinisation de la lumière duodénale et de la bile dans la vésicule biliaire. Nous avons montré une surexpression de VIP qui a un effet myorelaxant sur la vésicule biliaire, un défaut de vidange vésiculaire, une diminution de l expression des gènes activés par les acides biliaires (AB) et des transporteurs des ABs dans l'iléon, et une diminution de la proportion des ABs secondaires dans le foie, la bile et le sang portal. Nous proposons un modèle selon lequel le défaut de vidange vésiculaire interrompt le cycle entérohépatique des ABs tout en maintenant au moins partiellement le recyclage des ABs vers le foie via un shunt cholécystohépatique qui a été confirmé par l injection d un AB fluorescent dans la vésicule biliaire. Chez des souris cftrtm1Unc mais congéniques et soumises à un régime riche en lipides, le maintien de vidange vésiculaire est associée à une proportion plus élevée d ABs secondaires et au développement de lésions biliaires. Ainsi dans la mucoviscidose, le défaut de vidange vésiculaire et le shunt cholécystohépatique des ABs pourraient contribuer, du moins en partie, à la malabsorption des graisses et diminuer le risque de lésions hépatobiliaires, ce que nous souhaitons confirmer par de nouvelles approches expérimentales et cliniquesPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Métabolisme et toxicité des xénobiotiques dans l'épithélium biliaire

PARIS5-BU-Necker : Fermée (751152101) / SudocSudocFranceF

Régulation des fonctions de sécrétion de l'épithélium de la vésicule biliaire humaine par les acides biliaires

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF