期刊
MOLECULAR THERAPY
卷 26, 期 12, 页码 2779-2797出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2018.08.016
关键词
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资金
- 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]
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.
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