Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis.
Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis.
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DOI：
10.1002/hep.31211
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Gores GJ
中科院分区：
文献类型：
--
作者：
Azad AI;Krishnan A;Troop L;Li Y;Katsumi T;Pavelko K;Kostallari E;Guicciardi ME;Gores GJ
在胆汁淤积性肝病中，导管反应性（DR）细胞延伸到肝实质中并促进炎症和纤维化。我们之前观察到，与Mdr 2 −/−小鼠相比，缺乏肿瘤坏死因子相关凋亡诱导配体受体（Tr−/−）的多药耐药2（Mdr 2 −/−）双敲除（DKO）小鼠显示出更广泛的小管反应和肝纤维化。这一观察结果表明，DR-细胞群体的大小可能受到细胞凋亡的调节。为了检验这一概念，我们培养了从野生型（WT）、Tr−/−、Mdr 2 −/−和DKO小鼠中获得的上皮细胞粘附分子阳性反应性胆管细胞（ERCs）。WT和DKO ERC的单细胞转录组学和免疫染色证实了它们的DR细胞表型。此外，DKO ERC显示出独特的翻译簇，表达趋化因子，表明反应性状态。与WT相比，与骨髓细胞白血病1（MCL 1）抑制剂S63845（一种促凋亡BH 3模拟疗法）一起孵育可显著降低DKO和Mdr 2 −/− ERC活力。静脉注射S63845可显著降低Mdr 2 −/−和DKO小鼠的DR细胞群以及炎症和肝纤维化标志物。此外，与未处理小鼠相比，经S63845处理的DKO小鼠显示肝B淋巴细胞显著减少，如通过飞行时间的高清晰度质谱细胞术所评估。骨髓来源的巨噬细胞与来自DKO小鼠肝脏的ERC的共培养上调了B细胞定向趋化因子（C-C基序）配体5的表达。最后，在原发性硬化性胆管炎肝脏标本中，DR细胞在体外和体内被Bcl-2同源拮抗剂/杀伤剂激活后引发凋亡。DR细胞似乎在招募免疫细胞到肝脏中以积极创造炎症和促纤维化微环境方面发挥关键作用。慢性胆汁淤积小鼠模型中MCL 1的药理学靶向作用可减少DR细胞和B细胞群以及肝纤维化。
In cholestatic liver diseases, ductular reactive (DR) cells extend into the hepatic parenchyma and promote inflammation and fibrosis. We have previously observed that multidrug-resistant 2 (Mdr2−/−) double knockout (DKO) mice lacking tumor necrosis factor–related apoptosis-inducing ligand receptor (Tr−/−) display a more extensive ductular reaction and hepatic fibrosis compared to Mdr2−/− mice. This observation suggests that the magnitude of the DR-cell population may be regulated by apoptosis. To examine this concept, we cultured epithelial cell adhesion molecule–positive reactive cholangioids (ERCs) obtained from wild-type (WT), Tr−/−, Mdr2−/− and DKO mice. Single-cell transcriptomics and immunostaining of both WT and DKO ERCs confirmed their DR-cell phenotype. Moreover, DKO ERCs displayed a unique translational cluster with expression of chemokines, indicating a reactive state. Incubation with the myeloid cell leukemia 1 (MCL1) inhibitor S63845, a proapoptotic BH3-mimetic therapy, significantly decreased DKO and Mdr2−/− ERC viability compared to WT. Intravenous administration of S63845 significantly reduced the DR-cell population and markers of inflammation and liver fibrosis in Mdr2−/− and DKO mice. Furthermore, DKO mice treated with S63845 displayed a significant decrease in hepatic B lymphocytes compared to untreated mice as assessed by high-definition mass cytometry by time-of-flight. Coculture of bone marrow–derived macrophages with ERCs from DKO mouse livers up-regulated expression of the B cell–directed chemokine (C-C motif) ligand 5. Finally, DR cells were noted to be primed for apoptosis with Bcl-2 homologous antagonist/killer activation in vitro and in vivo in primary sclerosing cholangitis liver specimens. DR cells appear to play a key role in recruiting immune cells to the liver to actively create an inflammatory and profibrogenic microenvironment. Pharmacologic targeting of MCL1 in a mouse model of chronic cholestasis reduces DR-cell and B-cell populations and hepatic fibrosis.
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影响因子：
13.5
作者：
Clouston, AD;Powell, EE;Jonsson, JR
通讯作者：
Jonsson, JR
影响因子：
12.4
作者：
Adams JM;Cory S
通讯作者：
Cory S
DOI：
10.1056/nejmra1506330
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Lazaridis KN;LaRusso NF
通讯作者：
LaRusso NF
影响因子：
6
作者：
Fickert, Peter;Stoeger, Ulrike;Trauner, Michael
通讯作者：
Trauner, Michael
影响因子：
10.5
作者：
Dai H;Ding H;Meng XW;Peterson KL;Schneider PA;Karp JE;Kaufmann SH
通讯作者：
Kaufmann SH