Rosana Ottakandathil Babu1, Vincent Chi Hang Lui2, Yan Chen3, Rachel Sze Wan Yiu1, Yongqin Ye4, Ben Niu5, Zhongluan Wu6, Ruizhong Zhang3, Michelle On Na Yu7, Patrick Ho Yu Chung7, Kenneth Kak Yuen Wong7, Huimin Xia3, Michael Qi Zhang8, Bin Wang9, Urban Lendahl10, Paul Kwong Hang Tam11. 1. Dr. Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, The University of Hong Kong, Hong Kong. 2. Dr. Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, The University of Hong Kong, Hong Kong; Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. 3. Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. 4. Department of General Surgery, Shenzhen Children's Hospital, Shenzhen, Guangdong, China. 5. Department of Biological Sciences, Center for Systems Biology, The University of Texas at Dallas, Dallas, Texas, United States of America. 6. Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. 7. Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; Department of Surgery, University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China. 8. Department of Biological Sciences, Center for Systems Biology, The University of Texas at Dallas, Dallas, Texas, United States of America; MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, TNLIST, Tsinghua University, Beijing, China. 9. Department of General Surgery, Shenzhen Children's Hospital, Shenzhen, Guangdong, China. Electronic address: szwb1967@126.com. 10. Dr. Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, The University of Hong Kong, Hong Kong; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. Electronic address: urban.lendahl@ki.se. 11. Dr. Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, The University of Hong Kong, Hong Kong; Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; Department of Surgery, University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China. Electronic address: paultam@hku.hk.
Abstract
BACKGROUND AND AIMS: Biliary atresia (BA) is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. In this study, we aimed to investigate the underlying pathogenesis and molecular signatures associated with BA. METHODS: We combined organoid and transcriptomic analysis to gain new insights into BA pathobiology using patient samples and a mouse model of BA. RESULTS: Liver organoids derived from patients with BA and a rhesus rotavirus A-infected mouse model of BA, exhibited aberrant morphology and disturbed apical-basal organization. Transcriptomic analysis of BA organoids revealed a shift from cholangiocyte to hepatocyte transcriptional signatures and altered beta-amyloid-related gene expression. Beta-amyloid accumulation was observed around the bile ducts in BA livers and exposure to beta-amyloid induced the aberrant morphology in control organoids. CONCLUSION: The novel observation that beta-amyloid accumulates around bile ducts in the livers of patients with BA has important pathobiological implications, as well as diagnostic potential. LAY SUMMARY: Biliary atresia is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. Using human and mouse 'liver mini-organs in the dish', we unexpectedly identified beta-amyloid deposition - the main pathological feature of Alzheimer's disease and cerebral amyloid angiopathy - around bile ducts in livers from patients with biliary atresia. This finding reveals a novel pathogenic mechanism that could have important diagnostic and therapeutic implications.
BACKGROUND AND AIMS: Biliary atresia (BA) is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. In this study, we aimed to investigate the underlying pathogenesis and molecular signatures associated with BA. METHODS: We combined organoid and transcriptomic analysis to gain new insights into BA pathobiology using patient samples and a mouse model of BA. RESULTS: Liver organoids derived from patients with BA and a rhesus rotavirus A-infectedmouse model of BA, exhibited aberrant morphology and disturbed apical-basal organization. Transcriptomic analysis of BA organoids revealed a shift from cholangiocyte to hepatocyte transcriptional signatures and altered beta-amyloid-related gene expression. Beta-amyloid accumulation was observed around the bile ducts in BA livers and exposure to beta-amyloid induced the aberrant morphology in control organoids. CONCLUSION: The novel observation that beta-amyloid accumulates around bile ducts in the livers of patients with BA has important pathobiological implications, as well as diagnostic potential. LAY SUMMARY:Biliary atresia is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. Using human and mouse 'liver mini-organs in the dish', we unexpectedly identified beta-amyloid deposition - the main pathological feature of Alzheimer's disease and cerebral amyloid angiopathy - around bile ducts in livers from patients with biliary atresia. This finding reveals a novel pathogenic mechanism that could have important diagnostic and therapeutic implications.
Authors: Nimish Godbole; Iiris Nyholm; Maria Hukkinen; Joseph R Davidson; Athanasios Tyraskis; Jouko Lohi; Päivi Heikkilä; Katja Eloranta; Marjut Pihlajoki; Mark Davenport; Markku Heikinheimo; Antti Kyrönlahti; Mikko P Pakarinen Journal: Sci Rep Date: 2022-05-04 Impact factor: 4.996
Authors: Hongyu Lyu; Yongqin Ye; Vincent Chi Hang Lui; Weifang Wu; Patrick Ho Yu Chung; Kenneth Kak Yuen Wong; Hung-Wing Li; Man Shing Wong; Paul Kwong Hang Tam; Bin Wang Journal: Front Surg Date: 2022-09-05