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Cell Stem Cell. 2016 Jun 2;18(6):809-16. doi: 10.1016/j.stem.2016.05.005.

In Vivo Hepatic Reprogramming of Myofibroblasts with AAV Vectors as a Therapeutic Strategy for Liver Fibrosis.

Author information

1
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
2
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.
3
Department of Infectious Diseases, Heidelberg University Hospital, Cluster of Excellence CellNetworks, BioQuant BQ0030, D-69120 Heidelberg, Germany.
4
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.
5
Department of Medicine, Columbia University, New York, NY 10032, USA.
6
Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
7
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.

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.

PMID:
27257763
PMCID:
PMC5325707
DOI:
10.1016/j.stem.2016.05.005
[Indexed for MEDLINE]
Free PMC Article

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