The interplay of the Notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis

被引:108
作者
Bansal, Ruchi [1 ]
van Baarlen, Joop [2 ]
Storm, Gert [1 ,3 ]
Prakash, Jai [1 ]
机构
[1] Univ Twente, Fac Sci & Technol, MIRA Inst Biomed Technol & Tech Med, Targeted Therapeut,Dept Biomat Sci & Technol, NL-7522 NB Enschede, Netherlands
[2] Lab Pathol Oost Nederland, NL-7555 BB Hengelo, Netherlands
[3] Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut, NL-3584 CG Utrecht, Netherlands
关键词
FIBROSIS; ACTIVATION; POLARIZATION; PLASTICITY; DEPOSITION; INJURY; ROLES;
D O I
10.1038/srep18272
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
Hepatic stellate cells (HSCs) known as "master producers" and macrophages as "master regulators", are the key cell types that strongly contribute to the progression of liver fibrosis. Since Notch signaling regulates multiple cellular processes, we aimed to study the role of Notch signaling in HSCs differentiation and macrophages polarization and to evaluate its implication in liver fibrogenesis. Notch pathway components were found to be significantly upregulated in TGF beta-activated HSCs, inflammatory M1 macrophages, and in mouse and human fibrotic livers. Interestingly, inhibition of Notch using a selective gamma-secretase inhibitor, Avagacestat, significantly inhibited TGF beta-induced HSC activation and contractility, and suppressed M1 macrophages. Additionally, Avagacestat inhibited M1 driven-fibroblasts activation and fibroblasts-driven M1 polarization (nitric oxide release) in fibroblasts and macrophages co-culture, and conditioned medium studies. In vivo, post-disease treatment with Avagacestat significantly attenuated fibrogenesis in CCl4-induced liver fibrosis mouse model. These effects were attributed to the reduction in HSCs activation, and inhibition of inflammatory M1 macrophages and upregulation of suppressive M2 macrophages. These findings suggest that Notch signaling plays a crucial role in HSC activation and M1/M2 polarization of macrophages in liver fibrosis. These results provide new insights for the development of novel therapies against liver fibrosis through modulation of Notch signaling.
引用
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页数:12
相关论文
共 42 条
[1]
Notch signaling: simplicity in design, versatility in function [J].
Andersson, Emma R. ;
Sandberg, Rickard ;
Lendahl, Urban .
DEVELOPMENT, 2011, 138 (17) :3593-3612
[2]
Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans [J].
Bielesz, Bernhard ;
Sirin, Yasemin ;
Si, Han ;
Niranjan, Thiruvur ;
Gruenwald, Antje ;
Ahn, Seonho ;
Kato, Hideki ;
Pullman, James ;
Gessler, Manfred ;
Haase, Volker H. ;
Susztak, Katalin .
JOURNAL OF CLINICAL INVESTIGATION, 2010, 120 (11) :4040-4054
[3]
Notch signaling in development and cancer [J].
Bolos, Victoria ;
Grego-Bessa, Joaquin ;
de la Pompa, Jose Luis .
ENDOCRINE REVIEWS, 2007, 28 (03) :339-363
[4]
Activated hepatic stellate cells mediate the differentiation of macrophages [J].
Chang, Jonathan ;
Hisamatsu, Tadakazu ;
Shimamura, Katsuyoshi ;
Yoneno, Kazuaki ;
Adachi, Masayuki ;
Naruse, Hiroshi ;
Igarashi, Toru ;
Higuchi, Hajime ;
Matsuoka, Katsuyoshi ;
Kitazume, Mina T. ;
Ando, Setsu ;
Kamada, Nobuhiko ;
Kanai, Takanori ;
Hibi, Toshifumi .
HEPATOLOGY RESEARCH, 2013, 43 (06) :658-669
[5]
Inhibition of Notch Signaling by a γ-Secretase Inhibitor Attenuates Hepatic Fibrosis in Rats [J].
Chen, Yixiong ;
Zheng, Shaoping ;
Qi, Dan ;
Zheng, Shaojiang ;
Guo, Junli ;
Zhang, Shuling ;
Weng, Zhihong .
PLOS ONE, 2012, 7 (10)
[6]
Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair [J].
Duffield, JS ;
Forbes, SJ ;
Constandinou, CM ;
Clay, S ;
Partolina, M ;
Vuthoori, S ;
Wu, SJ ;
Lang, R ;
Iredale, JP .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (01) :56-65
[7]
Mechanisms of hepatic fibrogenesis [J].
Friedman, Scott L. .
GASTROENTEROLOGY, 2008, 134 (06) :1655-1669
[8]
Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver [J].
Friedman, Scott L. .
PHYSIOLOGICAL REVIEWS, 2008, 88 (01) :125-172
[9]
Hepatic fibrosis-Overview [J].
Friedman, Scott L. .
TOXICOLOGY, 2008, 254 (03) :120-129
[10]
Emerging Roles of Notch Signaling in Liver Disease [J].
Geisler, Fabian ;
Strazzabosco, Mario .
HEPATOLOGY, 2015, 61 (01) :382-392