生物
衰老
脂肪性肝炎
重编程
内皮
平衡
炎症
非酒精性脂肪性肝炎
细胞生物学
内分泌学
内科学
非酒精性脂肪肝
脂肪肝
免疫学
医学
细胞
生物化学
疾病
作者
Juan-Li Duan,Jingjing Liu,Bai Ruan,Jian Ding,Zhiqiang Fang,Hao Xu,Ming-Hui Zou,Chen Xu,Zhiwen Li,Wei Du,Lin Wang
出处
期刊:Research Square - Research Square
日期:2022-06-14
标识
DOI:10.21203/rs.3.rs-1730358/v1
摘要
Abstract Aging leads to systemic metabolic disorders including nonalcoholic steatohepatitis (NASH). Here, we showed that aging-induced liver sinusoidal endothelial cell (LSEC) senescence accelerated liver sinusoid capillarization and promoted steatohepatitis by reprogramming liver endothelial zonation and inactivating pericentral endothelium-derived C-kit. Abrogation of endothelial C-kit triggered cellular senescence which disturbed LSEC homeostasis. During diet-induced NASH development, C-kit deletion aggravated hepatic steatosis and exacerbated NASH-associated fibrosis and inflammation. Mechanistically, CXCR4/SDF-1 signaling was inhibited by C-kit. Blocking CXCR4/SDF-1 signaling by AMD3100 abolished LSEC-macrophage crosstalk and recovered the aggravated NASH in C-kit deficient mice. For therapeutic purpose, C-kit + LSECs were implanted into NASH or aged mice, which counteracted LSEC senescence and improved diet or aging-induced NASH by restoring the homeostasis of pericentral liver endothelium.
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