Periodic Reporting for period 4 - New Chol (Development of New therapies against cholangiopathies.)
Período documentado: 2022-06-01 hasta 2022-06-30
Cholangiopathies regroup diseases affecting cholangiocytes which are the main cell type of the biliary tract. These disorders range from inherited (Cystic Fibrosis) and developmental (Alagille Syndrome, Biliary Atresia) to autoimmune (Primary Biliary Cirrhosis), idiopathic (Primary Sclerosing Cholangitis) and drug or toxin induced diseases. Cholangiopathies result in toxic bile accumulation in the liver inducing cell death and ultimately cirrhosis. They carry high morbidity and mortality, accounting for up to a third of chronic liver disorders. Whole liver transplantation remains the main treatment. However, organ transplant requires immunosuppression with significant side effects and an increasing number of patients die while on the transplant list due to the shortage of suitable donors. Finally, the absence of physiologically relevant in vitro systems to model and to study cholangiopathies prevents the development of new therapeutics while cell based therapy approach have been unexplored. Here, we propose to systematically address these challenges by developing a novel and innovative program of translational research focusing on cholangiopathies. We will first investigate the cellular and functional diversity of the biliary tract and its impact on disease by taking advantage of recent developments in single cell transcriptomic analyses. We will then use this basic knowledge to generate and to characterize for the first time a renewable source of cholangiocytes from human induced pluripotent stem cells and from biliary tissue. The resulting cells will be used to model cholangiopathies in vitro and to create a new platform for drug target identification. Finally, we will explore the potential for in vitro generated cholangiocytes to be used in regenerative medicine applications including cell based therapy. Overall this comprehensive study will uniquely path the way for the development of a whole range of new therapies for cholangiopathies.
During the past 30 months, we have started to map the biliary epithelium at the single cell level. For that, we have collected primary tissues from different patients and from different regions of the biliary three and performed single cell transcriptomic. We have also performed similar experiments on cholangiocytes organoids derived from the same tissues or from human Pluripotent Stem Cells.These experiments have identified different subpopulation of cholangiocytes and identified new markers specific for each region of the biliary three. Comparative studies have also defined similarity and divergence between cells grown in vitro and their in vivo counterpart. Furthermore, we have started to perform single cell analyses on organoids derived from patients with different cholangiopathies. Finally, we are testing different animal model for biliary injury to demonstrate the capacity of in vitro generated organoids to repair biliary injury in vivo.
The data generated so provide the first single cell map of the biliary three. In addition we have derived an unique collection of organoid to model healthy and diseases tissue. Finally, we have now established a suitable animal model to test cell based therapy against cholangiopathies. The next step is to combine our single cell analyses to further understand divergence between cell grown in vitro and their in vivo counterparts. This information will be exploited to further improve in vitro culture conditions. Similarly, these analyses will help to understand disease mechanisms driving phenotypic divergences between Healthy and diseased organoids. Finally, we aim to establish the first proof of concept that cholangiocytes expended in vitro can be used to repair the biliary three after injury.
To conclude, the New-Chol project provides an unique program of translational research focusing on cholangiopathies. It will result in new knowledge regarding the physiology and physiopathology of the biliary tract. This information will allow the generation of a novel source of fully characterised cholangiocytes useful for the development of innovative platforms for basic studies and drug screening. Finally, this project will pave the way for cell-based therapies against cholangiopathies.
To conclude, the New-Chol project provides an unique program of translational research focusing on cholangiopathies. It will result in new knowledge regarding the physiology and physiopathology of the biliary tract. This information will allow the generation of a novel source of fully characterised cholangiocytes useful for the development of innovative platforms for basic studies and drug screening. Finally, this project will pave the way for cell-based therapies against cholangiopathies.