Faculté de médecine Pierre et Marie Curie – Site Saint-Antoine – 4ème étage
27, rue Chaligny – 75571 PARIS cedex 12
Summary: Objectives are to find new mechanisms, therapeutics and predictive tests of progression/regression in liver diseases that range from rare biliary diseases to the most common, chronic viral hepatitis and non-alcoholic fatty liver disease (NAFLD). Cohort studies aim to define the clinical spectrum and genetic heterogeneity of hereditary biliary diseases, notably those caused by gene defects in the phosphatidyl-choline transporter, ABCB4. The mechanisms of ABCB4 traffic and function, effects of missense variations and pharmacological rescue of variants are investigated, using 3D structure modeling, polarized cell models and transgenic mice. Pathogenesis and therapeutic targets are examined in genetic, chemical and dietary mouse models of liver disease with special interest in the pathways of cell death (necroptosis) and the direct impact of hepatitis B Virus (HBV) in the pathogenesis. The impact of bile acid homeostasis and gut microbiota on disease traits including hepatic encephalopathy, are analyzed in these models and patients. Studies on the origins and functions of liver myofibroblasts pertain to liver fibrosis and cancer. We investigate a sub-population of liver myofibroblasts derived from mesenchymal stem cells, which promote angiogenesis. New markers of this cell population are used for gene profiling in human and animal fibrotic livers, for cell fate-mapping and ultimately cell depletion, in transgenic mice. The contribution of cancer-associated myofibroblasts in the resistance of cholangiocarcinoma cells to targeted therapies, is addressed in co-cultures and xenograft models. The anti-steatotic, anti-viral (HBV), and anti-fibrotic potential of new molecules are tested in models including human liver cells, slices and perfused liver grafts (for transplantation) and in clinical trials of patients with biliary diseases, viral hepatitis B or NAFLD. Strategies combining serum tests (e.g., Fibrotest), elastometry and magnetic resonance imaging, are designed to assess fibrosis and predict primary liver cancer in these patients.
Doctoral Host Groups :
1- ABCB4 Pathobiology
Defects in the gene encoding the ductal transporter of phosphatidylcholine, ABCB4, cause cholestatic and cholelithiasic diseases of varying severity. The team's work has identified most of the genetic variations known to date in the ABCB4 gene. The formation of a national RADICO cohort is underway to conduct genotype-phenotype correlation and Next-Generation Sequencing (NGS) studies. The development of polarized cellular models and three-dimensional modelling allows us to study the impact of the variations identified in patients and to test molecules that allow us to correct the consequences of these mutations in order to ultimately propose targeted pharmacotherapy, from a personalized medicine perspective. Another aspect of the project aims to elucidate the molecular mechanisms that regulate membrane expression and function of the ABCB4 transporter, in particular by seeking interaction partners at its N-terminal end.
2- Cholangiopathies & Cholangiocarcinoma
Damage to the biliary epithelium or cholangiopathies results from alterations in the homeostasis of bile acids and intestinal microbiota, which can evolve into inflammation and fibrosis of the bile ducts, or even for certain biliary pathologies such as primary sclerosing cholangitis (PSC) to cholangiocarcinoma (CCA). In PSC, one of the therapeutic targets we are working on is the nuclear vitamin D receptor, which we have shown to have a protective role in the biliary epithelium. CCA is a cancer with a very poor prognosis, characterized by the presence of a contingent of cancer stem cells and an extremely fibrous stroma. Our work aims to study i/ the role of transcription factors of MMT in tumour cells and CFOs; ii/ sub-populations of CFOs; and iii/ the dialogue between tumour cells and CFOs, with an interest in extracellular vesicles as a major intercellular communication tool in pathophysiology. Finally, we are developing innovative therapies for cancer treatment with SU physicists as part of an interdisciplinary project.
3- Liver fibrosis & Cirrhosis
The severity of liver disease is largely related to the development of fibrosis. Our work showed that myofibroblasts, effector cells of fibrosis, were derived from at least two distinct cell populations, star cells and portal mesenchymal cells for which we identified a marker, collagen type XV, alpha 1 (COL15A1), as well as proliferative and pro-angiogenic properties. Ongoing work aims to 1) demonstrate that portal myofibroblasts are derived from mesenchymal stem cells and play a key role in the progression from fibrosis to cirrhosis; 2) determine the contribution of necroptosis, pro-inflammatory programmed cell death, to the progression of fibrosis, using mouse models; 3) elucidate the mechanisms of hepatic encephalopathy, a frequent and disabling complication of cirrhosis. Various non-invasive strategies are being evaluated to predict the stage of hepatic fibrosis, and to detect the complications of cirrhosis, particularly primary liver cancer, very early on.
3- Alternative splicing of hepatitis B virus (HBV) and liver pathogenesis
Our work has shown that the regulation of HBV transcripts by alternative splicing leads to the formation of circulating defective particles (HBVd) and the expression of a viral protein, identified by our group, the HBSP protein. The synthesis of HBVd is associated with the progression of liver damage to liver cancer. We have also established that HBSP deregulates the TNF signaling pathway and reduces inflammation and hepatic fibrogenesis through the recruitment of intrahepatic immune cells. Our research projects focus on 1) the correlation between the different circulating forms of HBV generated by spliced transcripts and clinical progression. 2) the role of HBSP protein in hepatic carcinogenesis. Our projects could lead to the development of new therapeutic strategies based on the biological properties of HBV.