Ectopic hepatocyte transplantation cures the pig model of tyrosinemia
Ectopic hepatocyte transplantation cures the pig model of tyrosinemia
Abstract The effectiveness of cell-based therapies to treat liver failure is limited by the diseased liver environment. Herein we provide preclinical proof-of-concept for the treatment of liver failure through hepatocyte transplantation into lymph nodes in a large-animal model of hereditary tyrosinemia type 1 (HT1), a metabolic liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH) enzyme. FAH-deficient pigs received autologous hepatocyte transplantation into mesenteric lymph nodes after ex vivo transduction with a lentiviral vector carrying the pig Fah gene. Hepatocytes showed early (6 hour) and durable (8 month) engraftment in lymph nodes, with reproduction of vascular and hepatic microarchitecture. Subsequently, hepatocytes migrated to and repopulated the native diseased liver. The corrected cells generated enough liver mass to clinically ameliorate disease as early as 97 days post-transplantation, with complete normalization of tyrosine levels and liver function tests. Integration site analysis defined the corrected hepatocytes in the liver as a subpopulation of hepatocytes in the lymph nodes, indicating that the lymph nodes served as a source for healthy hepatocytes to repopulate a diseased liver. Ectopic transplantation of hepatocytes cures the pig model of HT1 and presents a promising approach to the treatment of liver disease in patients with pre-existing liver damage and fibrosis. One Sentence SummaryTransplantation of corrected hepatocytes in mesenteric lymph nodes can cure fatal metabolic liver disease by providing organized liver tissue and by repopulating the diseased liver in the pig tyrosinemia model.
Jiang Huailei、Lagasse Eric、Lillegard Joseph B、Nicolas Clara T、Allen Kari L、VanLith Caitlin J、Bhagwate Aditya、Kocher Jean-Pierre A、Kaiser Robert A、Francipane Maria Giovanna、Cheikhi Amin、Lowe Val、Nyberg Scott L、Han Bing、DeGrado Timothy R、Amiot Bruce、Pandey Mukesh K、Guthman Rebekah M、Suksanpaisan Lukkana、Du Zeji、Hickey Raymond D、O?ˉBrien Daniel、Bansal Aditya、Garg Ishan
Department of Radiology, Mayo ClinicMcGowan Institute for Regenerative Medicine and Department of Pathology, University of PittsburghDepartment of Surgery, Mayo Clinic||Children?ˉs Hospitals and Clinics of Minnesota, Midwest Fetal Care Center||Pediatric Surgical AssociatesDepartment of Surgery, Mayo Clinic||Faculty of Medicine, University of Barcelona||Department of Surgery, University of Alabama BirminghamDepartment of Surgery, Mayo ClinicDepartment of Surgery, Mayo ClinicDepartment of Biomedical Statistics and Informatics, Mayo ClinicDepartment of Biomedical Statistics and Informatics, Mayo ClinicDepartment of Surgery, Mayo Clinic||Children?ˉs Hospitals and Clinics of Minnesota, Midwest Fetal Care CenterMcGowan Institute for Regenerative Medicine and Department of Pathology, University of Pittsburgh||Ri.MED FoundationDepartment of Physical Medicine and Rehabilitation, University of PittsburghDepartment of Radiology, Mayo ClinicDepartment of Surgery, Mayo ClinicMcGowan Institute for Regenerative Medicine and Department of Pathology, University of PittsburghDepartment of Radiology, Mayo ClinicDepartment of Surgery, Mayo ClinicDepartment of Radiology, Mayo ClinicDepartment of Surgery, Mayo Clinic||Medical College of WisconsinImanis Life SciencesDepartment of Surgery, Mayo ClinicDepartment of Surgery, Mayo Clinic||Department of Molecular Medicine, Mayo ClinicDepartment of Biomedical Statistics and Informatics, Mayo ClinicDepartment of Radiology, Mayo ClinicDepartment of Radiology, Mayo Clinic
医药卫生理论医学研究方法基础医学
Jiang Huailei,Lagasse Eric,Lillegard Joseph B,Nicolas Clara T,Allen Kari L,VanLith Caitlin J,Bhagwate Aditya,Kocher Jean-Pierre A,Kaiser Robert A,Francipane Maria Giovanna,Cheikhi Amin,Lowe Val,Nyberg Scott L,Han Bing,DeGrado Timothy R,Amiot Bruce,Pandey Mukesh K,Guthman Rebekah M,Suksanpaisan Lukkana,Du Zeji,Hickey Raymond D,O?ˉBrien Daniel,Bansal Aditya,Garg Ishan.Ectopic hepatocyte transplantation cures the pig model of tyrosinemia[EB/OL].(2025-03-28)[2025-05-10].https://www.biorxiv.org/content/10.1101/648493.点此复制
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