Comparison of Hepatic-like Cell Production from Human Embryonic Stem Cells and Adult Liver Progenitor Cells: CAR Transduction Activates a Battery of Detoxification Genes

In vitro production of human hepatocytes is of primary importance in basic research, pharmacotoxicology and biotherapy of liver diseases. We have developed a protocol of differentiation of human embryonic stem cells (ES) towards hepatocyte-like cells (ES-Hep). Using a set of human adult markers including CAAT/enhancer binding protein (C/EBPalpha), hepatocyte nuclear factor 4/7 ratio (HNF4alpha1/HNF4alpha7), cytochrome P450 7A1 (CYP7A1), CYP3A4 and constitutive androstane receptor (CAR), and fetal markers including alpha-fetoprotein, CYP3A7 and glutathione S-transferase P1, we analyzed the expression of a panel of 41 genes in ES-Hep comparatively with human adult primary hepatocytes, adult and fetal liver. The data revealed that after 21 days of differentiation, ES-Hep are representative of fetal hepatocytes at less than 20 weeks of gestation. The glucocorticoid receptor pathway was functional in ES-Hep. Extending protocols of differentiation to 4 weeks did not improve cell maturation. When compared with hepatocyte-like cells derived from adult liver non parenchymal epithelial (NPE) cells (NPE-Hep), ES-Hep expressed several adult and fetal liver makers at much greater levels (at least one order of magnitude), consistent with greater expression of liver-enriched transcription factors Forkhead box A2, C/EBPalpha, HNF4alpha and HNF6. It therefore seems that ES-Hep reach a better level of differentiation than NPE-Hep and that these cells use different lineage pathways towards the hepatic phenotype. Finally we showed that lentivirus-mediated expression of xenoreceptor CAR in ES-Hep induced the expression of several detoxification genes including CYP2B6, CYP2C9, CYP3A4, UDP-glycosyltransferase 1A1, solute carriers 21A6, as well as biotransformation of midazolam, a CYP3A4-specific substrate

De quelques réflexions sur l'Evolution et ses théories (suite)

Choisy M., Casoli-Mein Marie-Thérèse, Collardeau-Roux C. De quelques réflexions sur l'Evolution et ses théories (suite). In: Bulletin mensuel de la Société linnéenne de Lyon, 30ᵉ année, n°3, mars 1961. pp. 67-69

Expending the Phenotypic Spectrum of Encephalocraniocutaneous Lipomatosis: About a Prenatal Case With Complete Autopsy

International audienceEncephalocraniocutaneous lipomatosis (ECCL) or Haberland syndrome (MIM #613001) is a rare congenital neurocutaneous disorder. It is characterized by unilateral ocular, cutaneous and central nervous system anomalies. Key clinical features include hairless fatty tissue nevus of the scalp, choristoma of the eye and intraspinal and intracerebral lipomas. We report one of the first cases diagnosed after termination of pregnancy at 35 WG, including antenatal and post-mortem imaging, complete autopsy and genetic analysis. Prenatal ultrasound and MRI of the third trimester showed multifocal spinal lesions and left lateral cerebral ventriculomegaly with cerebral atrophy. Diagnosis of ECCL was suggested at complete autopsy which revealed nevus psiloliparus of the scalp, facial hamartomas and intracranial and spinal lipomas. In addition, our case also exhibited a cardiac rhabdomyoma and a multicystic dysplastic kidney, both never reported to date in this syndrome. ECCL was confirmed by the identification of a postzygotic FGFR1 mutation. We reviewed the literature and discuss the pathogenesis of this syndrome

Endoscopic hybrid resection and under-water snare resection of symptomatic duodenal duplication cysts in children

No abstract availabl

Lipids Responsible for Intestinal or Hepatic Disorder: When to Suspect a Familial Intestinal Hypocholesterolemia?

International audienceFamilial intestinal hypocholesterolemias, such as abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, are rare genetic diseases that result in a defect in the synthesis or secretion of lipoproteins containing apolipoprotein B.In children, these conditions present with diarrhoea and growth failure, whereas adults present with neuromuscular, ophthalmological, and hepatic symptoms. Simple laboratory investigations have shown that diagnosis can be made from findings of dramatically decreased cholesterol levels, deficiencies in fat-soluble vitamins (mostly vitamin E), endoscopic findings of the characteristic white intestinal mucosa, and fat-loaded enterocytes in biopsy samples. Genetic analysis is used to confirm the diagnosis. Treatment is based on a low-fat diet with essential fatty acid supplementation, high doses of fat-soluble vitamins, and regular and life-long follow-up.The present study examines cases and literature findings of these conditions, and emphasises the need to explore severe hypocholesterolemia and deficiencies in fat-soluble vitamins to not miss these rare, but easy to diagnose and treat, disorders

Escherichia coli-associated hemolytic uremic syndrome and severe chronic hepatocellular cholestasis: complication or side effect of eculizumab?

BACKGROUND: Liver lesions of hemolytic uremic syndrome due to Shiga-toxin-producing Escherichia coli (STEC-HUS) are uncommon. CASE-DIAGNOSIS/TREATMENT: We report three observations of severe STEC-HUS with delayed hepatic involvement. They presented with multiple organ failure and received eculizumab; 15 days after the onset of STEC-HUS, cholestasis appeared and cytolysis worsened. Abdominal ultrasonography showed vesicular sludge. Liver biopsy performed 3 to 6 months after the STEC-HUS found cholangiolar proliferation and inflammatory portal fibrosis. Despite renal recovery, cholestasis persisted and worsened in two cases, leading to biliary cirrhosis and subsequent liver transplantation. Pathological examination of one native liver found thrombotic microangiopathy. CONCLUSIONS: Even though the pathological examination performed on one native liver demonstrated areas of thrombotic microangiopathy, we cannot completely rule out that eculizumab may have worsened the liver lesions. Before the efficacy of eculizumab in STEC-HUS is formally demonstrated, physicians should stay cautious in its use

Liver transplantation of partial grafts after ex situ splitting during hypothermic oxygenated perfusion-The HOPE-Split pilot study

International audiencePartial liver grafts from ex situ splitting are considered marginal due to prolonged static cold storage. The use of ex situ hypothermic oxygenated perfusion (HOPE) may offer a strategy to improve preservation of ex situ split grafts. In this single-center pilot study, we prospectively performed ex situ liver splitting during HOPE (HOPE-Split) for adult and pediatric partial grafts over a 1-year period (November 1, 2020 to December 1, 2021). The primary safety endpoint was based on the number of liver graft-related adverse events (LGRAEs) per recipient, including primary nonfunction, biliary complications, hepatic vascular complications, and early relaparotomies and was compared with consecutive single-center standard ex situ split transplantations (Static-Split) performed from 2018 to 2020. Secondary endpoints included preservation characteristics and early outcomes. Sixteen consecutive HOPE-Split liver transplantations (8 HOPE-Split procedures) were included and compared with 24 Static-Splits. All HOPE-Split grafts were successfully transplanted, and no graft loss nor recipient death was encountered during the median follow-up of 7.5 months (interquartile range, 5.5-12.5). Mean LGRAE per recipient was similar in both groups (0.31 ± 0.60 vs. 0.46 ± 0.83; p = 0.78) and split duration was not significantly increased for HOPE-Split (216 vs. 180 min; p = 0.45). HOPE-Split grafts underwent perfusion for a median of 125 min, which significantly shortened static cold storage (472 vs. 544 min; p = 0.001), whereas it prolonged total ex vivo preservation (595 vs. 544 min; p = 0.007) and reduced neutrophil infiltration on reperfusion biopsies (p = 0.04) compared with Static-Split. This clinical pilot study presents first feasibility and safety data for transplantation of partial liver grafts undergoing ex situ split during HOPE and suggests improved preservation compared with static ex situ splitting. These preliminary results will allow to set up large-scale trials on the use of machine perfusion in pediatric and split-liver transplantation

Prenatal imaging features suggestive of liver gestational allo immune disease

International audienceWe report prenatal imaging features of four cases of neonatal hemochromatosis due to an alloimmune disease. All cases exhibited intra uterine growth restriction (IUGR) without arguments for a vascular etiology, associated with oligohydramnios. Placental hydrops was present in 75% of cases. Splenomegaly was identified in one case. Other causes of NH have been ruled out during diagnostic workup including karyotype, detection of IGFBP-1 to evaluate a premature rupture of membranes, maternal serologic tests. MRI was performed in two cases and showed an atrophic liver associated with a low signal intensity on T2-sequence in one case. Prenatal NH was suspected in this later case and the fetus was successfully treated with two IVIG (intravenous immunoglobulins) perfusions performed during pregnancy followed by exchange transfusion and IVIG after birth. The child is doing well with normal liver function tests after 17 months of follow up. Our aim was to highlight the importance of suggesting NH-GALD when facing IUGR with oligohydramnios, ascites, placental hydrops, splenomegaly on prenatal ultrasound with negative work up for placental vascular pathologies and infectious fetopathies. MRI might be of a good help, showing an atrophic liver but enhancing iron overload in hepatic and extrahepatic tissue is helpful but not constant