Etienne M Sokal

• MD,PhD
• Head of Department at Cliniques Universitaires Saint-Luc, Université Catholique de Louvain

Liver cell therapy (LCT) is a procedure where cells rather than organs are transplanted in a patient affected by a liver-based inborn error of metabolism (IEM) or an acquired liver disease. It has been developed to overcome the limitations of liver transplantation (LT), mainly organ shortage. Initially, fresh hepatocytes isolated from livers not su...

Our clinical center has pioneered the organ and cell transplantation approaches to treat Zellweger spectrum disorders (ZSD). The present work aimed to develop innovative tools to evaluate peroxisome biogenesis (PB) in vitro and in a pre-clinical model, in order to assess the potential benefit of hepatocyte transplantation in ZSD. ZSD are inborn err...

Peroxisomes are ubiquitous organelles formed by peroxisome biogenesis (PB). During PB, peroxisomal matrix proteins harboring a peroxisome targeting signal (PTS) are imported inside peroxisomes by peroxins, encoded by PEX genes. Genetic alterations in PEX genes lead to a spectrum of incurable diseases called Zellweger spectrum disorders (ZSD). In vi...

Since January 2020, the Novel Coronavirus Disease 2019 (COVID-19) pandemic has dramatically impacted the world. In March 2020, the COVID-19 epidemic reached Belgium creating uncertainty towards all aspects of life. There has been an impressive capacity and solidarity of all healthcare professionals to acutely reconvert facilities to treat these pat...

Background: Hepatitis C virus is one of the leading causes of chronic liver disease and liver-related deaths worldwide. The estimated prevalence of chronic hepatitis C viral infection among the general Belgian population was 0.57% (n = 64,000) in 2015. Although Belgium has had a 'Hepatitis C Plan' since 2014, elimination efforts are unclear. This...

Familial hypocalciuric hypercalcemia is an autosomal dominant genetic disorder characterized by hypercalcemia associated with inappropriate hypocalciuria and normal parathyroid hormone levels. Acute recurrent pancreatitis (ARP) is rare in children. Predisposing factors include hypercalcemia and mutations in the serine protease inhibitor Kazal-type...

Adipose tissue‐derived mesenchymal stromal cells (ASCs) hold the promise of achieving successful immunotherapeutic results due to their ability to regulate different T‐cell fate. ASCs also show significant adaptability to environmental stresses by modulating their immunologic profile. Cell‐based therapy for inflammatory diseases requires a detailed...

Objectives Cirrhotic children wait‐listed for liver transplant are prone to bleeding from gastrointestinal varices. Grade 2‐3 esophageal varices, red signs, and gastric varices are well‐known risk factors. However, the involvement of hemostatic factors remains controversial because of the rebalanced state of coagulation during cirrhosis. Methods C...

Objective and design The objective of the study is to uncover the influence of human bone marrow-derived mesenchymal stem cells (BM-MSCs) on the generation of Th17 lymphocytes in co-cultures of both BM-MSCs and T cells. Materials and methods BM-MSCs, characterized according to the international society for cellular therapy (ISCT) criteria, were co...

Most tumours have an aberrantly activated lipid metabolism1,2 that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation³. This suggests that many cancer cells...

Background and aim: Patients with methylmalonic acidemia (MMA) and propionic acidemia (PA) and urea cycle disorders (UCD), treated with a protein restricted diet, are prone to growth failure. To obtain optimal growth and thereby efficacious protein incorporation, a diet containing the essential and functional amino acids for growth is necessary. O...

This paper on the biological tests carried out on serum/plasma samples from donors of human body material (HBM) is the result of a project of the working Group of Superior Health Council of Belgium formed with experts in the field of HBM and infectious serology. Indeed, uncertainty about the interpretation of biological test results currently leads...

The article Biological tests carried out on serum/plasma samples from donors of human body material for transplantation: Belgian experience and practical recommendations.

Nonalcoholic fatty liver disease (NAFLD) is an emerging entity, becoming the most prevalent pediatric chronic liver disease. Its broad spectrum of histological findings, comorbidities, and complications, including cirrhosis and liver failure, can occur in childhood, emphasizing the severity of pediatric NAFLD. Current lifestyle and diet modificatio...

In adults, treatment of hepatitis C virus (HCV) infection with ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) with or without dasabuvir (DSV) and ±ribavirin (RBV) results in high rates of sustained virologic response (SVR). However, these regimens have not been investigated in adolescents. This ongoing, open‐label, phase 2/3 study evaluated the...

Background: Ophthalmic abnormalities are amongst the 5 major criteria for diagnosing autosomal dominant Alagille Syndrome (AS). Embryotoxon, pseudo-papilledema and pigmentary retinopathy being most frequently part of the syndrome. Papilledema with or without intracranial hypertension (ICHT) are rarely described. We report 9 cases of bilateral papil...

Background: Being non-immunogenic and capable of achieving major metabolic liver functions, adult-derived human liver stem/progenitor cells (ADHLSCs) are of special interest in the field of liver cell therapy. The cytokine repertoire of engrafted cells may have critical impacts on the immune response balance, particularly during cell transplantati...

The development of complex in vitro hepatic systems and artificial liver devices has been hampered by the lack of reliable sources for relevant cell types, such as hepatic stellate cells (HSCs). Here we report efficient differentiation of human pluripotent stem cells into HSC-like cells (iPSC-HSCs). iPSC-HSCs closely resemble primary human HSCs at...

Hepatic fibrosis is a pathological lesion, characterized by the progressive accumulation of extracellular matrix (ECM) in the perisinusoidal space and it is a major problem in chronic liver diseases. Phenotypic activation of hepatic stellate cells (HSC) plays a central role in the progression of hepatic fibrosis. Retardation of proliferation and cl...

Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the ATP8B1 gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the ABCB11 gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary dive...

Supplementary Table 1. Growth post‐PEBD Supplementary Table 2. Clinically meaningful improvement in blood biochemistry post‐PEBD. Supplementary Table 3. Reported use of immunosuppressants post‐transplant. Supplementary Table 4. Relative odds of blood chemistry being abnormal, after recovery from LTX Supplementary Table 5. Height and weight after LT...

Despite the importance of vaccinating childrenyounger thn 5 years, few studies evaluating vaccine prevention of influenza have been reported in this age group. Martine Docx was a member of the Flu4VEC Study Group.

Mild Zellweger spectrum disorder, also described as Infantile Refsum disease, is attributable to mutations in PEX genes. Its clinical course is characterized by progressive hearing and vision loss, and neurodevelopmental regression. Supportive management is currently considered the standard of care, as no treatment has shown clinical benefits. LT w...

Background Despite the importance of vaccinating children younger than 5 years, few studies evaluating vaccine prevention of influenza have been reported in this age group. We evaluated efficacy of an inactivated quadrivalent influenza vaccine (IIV4) in children aged 6–35 months. Methods In this phase 3, observer-blinded, multinational trial, he...

Human hepatic stellate cells (HSCs) demonstrated great immunological plasticity with important consequences for liver cell therapy. Activated HSCs (aHSCs) are in vitro reverted (rHSCs) to a quiescent-like phenotype with potential benefit to reduce liver fibrosis. The goal of this study is to establish and compare the immunological profile of activa...

Sodium taurocholate cotransporter polypeptide (NTCP), mainly expressed on the sinusoidal membrane of hepatocytes, is one of the major transporters responsible for liver bile acid (BA) re‐uptake. NTCP transports conjugated BA from the blood into hepatocytes and is crucial for correct enterohepatic circulation. Studies have shown that insufficient he...

The liver has an important function in the human body and plays a crucial role in its metabolism. Orthotopic liver transplantation (OLT) is the gold standard treatment for patients presenting liver failure or end stage liver diseases, and is also applied for liver based intractable metabolic disorders. Due to organ shortage, invasive surgery and pe...

Background Hepatitis B virus (HBV) carriers worldwide number approximately 240 million people and around 780,000 people die every year from HBV infection. HBV entry and uptake are functionally linked to the presence of the human sodium-taurocholate cotransporting peptide (hNTCP) receptor. Recently, our group demonstrated that human umbilical cord m...

Children with chronic hepatitis B (CHB) represent an area of unmet medical need, attributed to increased lifetime risk of CHB sequelae and limited therapeutic options compared with adult CHB patients. The PEG-B-ACTIVE (NCT01519960) phase III study evaluated peginterferon (PegIFN) alfa-2a treatment in children aged 3 to <18 years with CHB. A total o...

Increasing evidence supports that modifications in the mitochondrial content, oxidative phosphorylation (OXPHOS) activity, and cell metabolism influence the fate of stem cells. However, the regulators involved in the crosstalk between mitochondria and stem cell fate remain poorly characterized. Here, we identified a transcriptional regulatory axis,...

Background: Antenatal therapy with high-dose intravenous immunoglobulin (IVIG) may prevent gestational alloimmune liver disease (GALD). Objective: The objective of this study was to determine the effectiveness of this approach in a large cohort of women at risk for poor pregnancy outcome due to GALD. Methods: Women with a history of affected o...

Background: Homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder, is characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerotic cardiovascular disease. Statin treatment starts at diagnosis, but no statin has been formally evaluated in, or approved for, HoFH children...

Background and Objectives The diagnostic role of endoscopic ultrasound (EUS) in children has been demonstrated only recently. Data on the technique’s therapeutic indications remain scarce. We evaluated diagnostic and interventional EUS indications, safety, and impact in children with pancreaticobiliary disorders. Patients and Methods We retrospect...

In a new report, adolescents with genotype 2 or 3 HCV infection who were given sofosbuvir and ribavirin showed a near 100% sustained virologic response. This study is the beginning of a new wave of treatments for paediatric HCV infection, forming part of a global strategy to eradicate viral hepatitis.

Background: Progressive liver fibrosis leads to cirrhosis and end-stage liver disease. This disease is a consequence of strong interactions between matrix-producing hepatic stellate cells (HSCs) and resident and infiltrating immune cell populations. Accumulated experimental evidence supports the involvement of adult-derived human liver mesenchymal...

The cardinal features of Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate (EEC), and Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndromes are ectodermal dysplasia (ED), orofacial clefting, and limb anomalies. EEC and AEC are caused by heterozygous mutations in the transcription factor p63 encoded by TP63. Here, we report a patien...

Chronic hepatitis C virus (HCV) infection is a major cause of cirrhosis, hepatocellular carcinoma and end-stage liver disease. One hundred thirty million to 150 million people have chronic HCV infection, among them 11 million are younger than 15 years of age. This review summarises the epidemiology and characteristics of HCV infection in children,...

Background: Alagille syndrome (AS) is an autosomal dominant multi-systemic disorder caused by pathogenic variants in JAG1 and NOTCH2. Characteristic findings include hepatic involvement with bile duct paucity and 20-50% eventually need a liver transplantation. Post-LT Tacrolimus induced nephropathy is well recognised and 40% of AS patients have an...

Preliminary data concerning human neonates and adult primary hepatocyte expression of HBV receptor NTCP is presented in this poster. These finding show that NTCP glycosilation and post translation modification is age dependent, and help to understand HBV vertical transmission in human neonates by HBV positive mothers.

Adult-derived human liver stem/progenitor cells (ADHLSCs) are, nowadays, developed as therapeutic medicinal product for the treatment of liver defects. In this study, the impact of hepatogenic differentiation and inflammation priming on the ADHLSCs’ immune profile was assessed in vitro and compared to that of mature hepatocytes. The constitutive im...

Background With the exception of liver transplantation, there is no cure for hemophilia, which is currently managed by preemptive replacement therapy. Liver-derived stem cells are in clinical development for inborn and acquired liver diseases and could represent a curative treatment for hemophilia A. The liver is a major factor VIII (FVIII) synthes...

Adult-derived human liver stem/progenitor cells (ADHLSCs) have the potential to alleviate liver injury. However, the optimal delivery route and long-term biodistribution of ADHLSCs remains unclear. In this paper, we used a triple fusion reporter system to determine the kinetic differences in the biodistribution of ADHLSCs following intrasplenic (IS...

There is growing evidence that cell therapy constitutes a promising strategy for liver regenerative medicine. In the setting of hepatic cancer treatments, cell therapy could prove a useful therapeutic approach for managing the acute liver failure that occurs following extended hepatectomy. In this study, we examined the influence of delivering adul...

Background: Proliferation of hepatic stellate cells (HSCs) plays a pivotal role in the progression of liver fibrosis consequent to chronic liver injury. Silibinin, a flavonoid compound, has been shown to possess anti-fibrogenic effects in animal models of liver fibrosis. This was attributed to an inhibition of cell proliferation of activated HSCs....

Zellweger spectrum disorders (ZSD) are peroxisome biogenesis disorders (PBD) attributable to mutations in PEX genes that lead to metabolites accumulation (phytanic acid, …). Supportive management is currently considered the standard of care, since no treatment has showed clinical benefits. Adult-Derived Human Liver Stem Cells (ADHLSCs) are isolated...

ADHLSCs were sequentially incubated with specific growth factors/cytokines and processed for the evaluation of the hepatogenic differentiation quality. A) Differentiated ADHLSC display significant morphological changes with polygonal epithelial-like shape. Pictures were taken at magnification of 200x. Presented data are representative of at least t...

Histological quantification of apha smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients Varma S1, Stephenne X1, Komuta M2, Bouzin.C3, Ambroise J4, Smets F1, Reding R5, and Sokal EM1 Universite Catholique de Louvain, Cliniques Universitaires St Luc, 1Service de Gastroenterologie et Hepatologie Pediatrique and...

Allograft inflammation and fibrosis among maintenance pediatric liver transplant recipients – genetic predisposition and antibodies, connecting the missing links. Varma S1, Latinne D2, Komuta M3, Ambroise J4, Smets F1, Baldin P3,Reding R5 , Stephenne X1, and Sokal EM1 Universite Catholique de Louvain, Cliniques Universitaires St Luc, 1Service de Ga...

Hepatitis B virus infection is still a major public health problem worldwide, since more than 350 million people have chronic, lifelong infection and nearly 1 million deaths occur each year owing to complications. Most infections are acquired at birth or during early childhood. Nowadays, low- and middle-income countries bear the majority of the bur...

Aim: Uncertainty about the safety of cell therapy continues to be a major challenge to the medical community. Inflammation and the associated immune response represent a major safety concern hampering the development of long-term clinical therapy. In vivo interactions between the cell graft and the host immune system are mediated by functional env...

Mesenchymal stromal cells (MSCs) are known to have potential therapeutic benefits for a number of diseases. However, many studies report low engraftment levels, regardless of the target organ. One possible explanation could be that MSCs do not express the necessary receptors for engraftment. Indeed, MSCs appear to use a similar mechanism to leukocy...

Activated hepatic stellate cells express cytoplasmic ASMA prior to secreting collagen and consequent liver fibrosis. We hypothesized that quantifying ASMA could predict severity of future fibrosis after LT. For this, 32 pairs of protocol biopsies, that is, “baseline” and “follow-up” biopsies taken at 1- to 2-year intervals from 18 stable pediatric...

Cyclosporine A, a potent calcineurin inhibitor, has been widely used in organ transplantation and in the treatment of autoimmune diseases. It has however been shown to induce serious renal and hepatic side effects. The drug is also used in preclinical studies, but with little published information on the optimal dose and route of administration in...

Glycogen storage diseases (GSD) are inherited metabolic diseases characterized by glycogen accumulation in the liver and/or muscles. Among liver GSDs, glycogen phosphorylase-phosphorylase kinase deficiency is responsible for GSD Type IX or VI. GSD Type IX results from a glycogen phosphorylase kinase deficiency and is primarily caused by a damage to...

Document S1. Supplemental Experimental Procedures, Figures S1–S5, and Tables S1–S3

Significance: β-cell replacement therapy represents the most promising approach to restore glucose homeostasis in patients with type 1 diabetes. This study shows an innovative and robust in vitro system for large-scale production of β-like cells from human pancreatic duct-derived cells (HDDCs) using a nonintegrative RNA-based reprogramming techniq...

Although pluripotent stem cells can be differentiated into the hepatocyte lineages, such cells retain an immature phenotype. As the chromatin state of regulatory regions controls spatiotemporal gene expression during development, we evaluated changes in epigenetic histone marks in lineage-specific genes throughout in vitro hepatocyte differentiatio...

Statement of the problem: Prevalence of Human-Immunodeficiency-Virus/Hepatitis-B-virus (HIV/HBV) coinfection and HBV vaccination response in children are unknown in KwaZulu-Natal. Method of the study: This study included 183 HIV-infected and 108 HIV-uninfected children aged between 5 and 15 years screened for HBV infection and vaccination. Resu...

Thorough research on the capacity of human islet transplantation to cure type 1 diabetes led to the achievement of 3- to 5-year-long insulin independence in nearly half of transplanted patients. Yet, translation of this technique to clinical routine is limited by organ shortage and the need for long-term immunosuppression, restricting its use to ad...

Chronic hepatitis B virus (HBV) infection and HBV-related hepatitis in children remains an unmet medical need, as current treatments are only partially effective, and only in a limited number of affected children. So-called "immunotolerant" children have not shown increased serological responses to available treatments. In cases involving more acti...

Aim: To determine predisposing factors of idiopathic allograft fibrosis among pediatric liver transplant recipients. Background: Protocol biopsies (PB) from stable liver transplant (LT) recipient children frequently exhibit idiopathic fibrosis. The relation between allograft inflammation, humoral immune response and fibrosis is uncertain. Also the...

Histological characteristics of protocol biopsies.

Clinical and demographic data of included children.

Statistical analysis of Portal Fibrosis (LAFSc-P) evolution in successive Protocol Biopsies (PB) using a cumulative logistic mixed-effect model.