title: In Vivo Hepatic Reprogramming of Myofibroblasts with AAV Vectors as a Therapeutic Strategy for Liver Fibrosis.
abstract: Liver fibrosis, a form of scarring, develops in chronic liver diseases when hepatocyte regeneration cannot compensate for hepatocyte death. Initially, collagen produced by myofibroblasts (MFs) functions to maintain the integrity of the liver, but excessive collagen accumulation suppresses residual hepatocyte function, leading to liver failure. As a strategy to generate new hepatocytes and limit collagen deposition in the chronically injured liver, we developed in vivo reprogramming of MFs into hepatocytes using adeno-associated virus (AAV) vectors expressing hepatic transcription factors. We first identified the AAV6 capsid as effective in transducing MFs in a mouse model of liver fibrosis. We then showed in lineage-tracing mice that AAV6 vector-mediated in vivo hepatic reprogramming of MFs generates hepatocytes that replicate function and proliferation of primary hepatocytes, and reduces liver fibrosis. Because AAV vectors are already used for liver-directed human gene therapy, our strategy has potential for clinical translation into a therapy for liver fibrosis.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Milad
authors.initials: M
authors.lastname: Rezvani
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Español-Suñer
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Yann
authors.initials: Y
authors.lastname: Malato
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Laure
authors.initials: L
authors.lastname: Dumont
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grimm
authors.affiliation: Department of Infectious Diseases, Heidelberg University Hospital, Cluster of Excellence CellNetworks, BioQuant BQ0030, D-69120 Heidelberg, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Kienle
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jay G
authors.initials: JG
authors.lastname: Bindman
authors.affiliation: Department of Infectious Diseases, Heidelberg University Hospital, Cluster of Excellence CellNetworks, BioQuant BQ0030, D-69120 Heidelberg, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Wiedtke
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Bernadette Y
authors.initials: BY
authors.lastname: Hsu
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Syed J
authors.initials: SJ
authors.lastname: Naqvi
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
authors.affiliation: Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Carlos U
authors.initials: CU
authors.lastname: Corvera
authors.affiliation: Department of Infectious Diseases, Heidelberg University Hospital, Cluster of Excellence CellNetworks, BioQuant BQ0030, D-69120 Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Grimm
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Surgery, Division of Transplantation, University of California, San Francisco, San Francisco, CA 94143, USA; Liver Center, University of California, San Francisco, San Francisco, CA 94110, USA. Electronic address: willenbringh@stemcell.ucsf.edu.
authors.forename: Holger
authors.initials: H
authors.lastname: Willenbring
mesh_terms: D000818:Animals; D002213:Capsid / Q000378:metabolism; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D000229:Dependovirus / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000378:metabolism*; D008099:Liver / Q000166:cytology*; D008103:Liver Cirrhosis / Q000473:pathology* / Q000628:therapy*; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000166:cytology*