Journal
MOLECULAR THERAPY
Volume 26, Issue 12, Pages 2779-2797Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2018.08.016
Keywords
-
Categories
Funding
- National Key R&D Program of China [2018YFA0507502, 2016YFC0902400, 2017YFC0906603]
- Chinese State Key Projects for Basic Research (973 Program) [2014CBA02001]
- National Natural Science Foundation of China [81770581, 81570526, 81123001]
- Beijing Science and Technology Project [Z161100002616036]
- Open Project Program of the State Key Laboratory of Proteomics (Academy of Military Medical Sciences) [SKLP-O201509]
- Innovation project [16CXZ027]
Ask authors/readers for more resources
Liver sinusoidal endothelial cells (LSECs) have great capacity for liver regeneration, and this capacity can easily switch to profibrotic phenotype, which is still poorly understood. In this study, we elucidated a potential target in LSECs for regenerative treatment that can bypass fibrosis during chronic liver injury. Proregenerative LSECs can be transformed to profibrotic phenotype after 4 weeks of carbon tetrachloride administration or 10 days of bile duct ligation. This phenotypic alternation of LSECs was mediated by extracellular regulated protein kinases 1 and 2 (Erk1/2)-Akt axis switch in LSECs during chronic liver injury; Erk1/2 was normally associated with maintenance of the LSEC proregenerative phenotype, inhibiting hepatic stellate cell (HSC) activation and promoting tissue repair by enhancing nitric oxide (NO)/reactive oxygen species (ROS) ratio and increasing expression of hepatic growth factor (HGF) and Wingless-type MMTV integration site family member 2 (Wnt2). Alternatively, Akt induced LSEC profibrotic phenotype, which mainly stimulated HSC activation and concomitant senescence by reducing NO/ROS ratio and decreasing HGF/Wnt2 expression. LSEC-targeted adenovirus or drug particle to promote Erk1/2 activity can alleviate liver fibrosis, accelerate fibrosis resolution, and enhance liver regeneration. This study demonstrated that the Erk1/2-Akt axis acted as a switch to regulate the proregenerative and profibrotic phenotypes of LSECs, and targeted therapy promoted liver regeneration while bypassing fibrosis, providing clues for a more effective treatment of liver diseases.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available