Biliary atresia (BA) is the most common cause of pediatric end-stage liver disease in the U.S. However, there is no effective treatment for BA due to a lack of human cellular model of the disease that would facilitate mechanistic studies or development of potential drugs and prevention strategies. In order to overcome this hurdle, we have successfully generated multiple patient-specific induced pluripotent stem cell (iPSC) lines from BA patients. We have also created a panel of isogenic human iPSC lines with precise genome editing at reported BA susceptibility loci. Based on these BA-relevant human iPSC lines and our expertise on recapitulating early human hepatic and biliary organ development from iPSCs, we propose to develop the first disease-relevant human model for understanding molecular basis of early BA development. Our preliminary results have indicated an altered biliary differentiation in the BA-iPSC lines. This study aims at further validating the disease model by characterizing the functional defects in hepatobiliary differentiation stages. We also aim to identify key pathways responsible for BA development by RNA-Seq analyses. Completion of this study will significantly enhance our understanding of human biliary system development. The BA model developed in this study will provide a powerful tool and a novel assay platform to study the genetic basis of developmental defects in BA, to understand the interactions between genetic and environmental risk factors and to develop potential drug treatments.
This study aims to establish a disease-relevant human cellular model of Biliary Atresia that recapitulates the abnormal early hepatobiliary development. The disease model developed in this study will provide a powerful tool and a novel assay platform to study the genetic basis of developmental defects in Biliary Atresia, to understand the interactions between genetic and environmental risk factors and to develop potential drug treatments.
| Tian, Lipeng; Ye, Zhaohui; Kafka, Kim et al. (2018) Biliary Atresia Relevant Human iPSCs Recapitulate Key Disease Features in a Dish. J Pediatr Gastroenterol Nutr : |
