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In Vivo Hepatic Reprogramming of Myofibroblasts with AAV Vectors as a Therapeutic
Strategy for Liver Fibrosis
#MMPMID27257763
Rezvani M
; Español-Suñer R
; Malato Y
; Dumont L
; Grimm AA
; Kienle E
; Bindman JG
; Wiedtke E
; Hsu BY
; Naqvi SJ
; Schwabe RF
; Corvera CU
; Grimm D
; Willenbring H
Cell Stem Cell
2016[Jun]; 18
(6
): 809-816
PMID27257763
show ga
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.
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