Paracrine cellular senescence exacerbates biliary injury and impairs regeneration.
Paracrine cellular senescence exacerbates biliary injury and impairs regeneration.
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DOI：
10.1038/s41467-018-03299-5
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发表时间：
2018-03-09
影响因子：
16.6
通讯作者：
Forbes SJ
中科院分区：
文献类型：
--
作者：
Ferreira-Gonzalez S;Lu WY;Raven A;Dwyer B;Man TY;O'Duibhir E;Lewis PJS;Campana L;Kendall TJ;Bird TG;Tarrats N;Acosta JC;Boulter L;Forbes SJ
细胞衰老是为细胞周期进程提供不可逆屏障以防止不期望的增殖的机制。然而，在病理情况下，衰老会对器官功能、活力和再生产生不利影响。我们开发了一种胆汁衰老小鼠模型，该模型基于Krt 19启动子控制下胆管中Mdm2的条件性缺失，表现出胆汁疾病的特征。我们在此报道衰老的胆管细胞诱导细胞和信号微环境的深刻改变，肌成纤维细胞和巨噬细胞的募集引起胶原沉积，TGFβ产生并诱导周围胆管细胞和肝细胞的衰老。最后，我们研究了TGFβ信号的抑制如何破坏衰老的传递并恢复肝功能。我们确定细胞衰老是胆道损伤发展中的一种有害机制。我们的研究结果确定TGFβ作为一个潜在的治疗靶点，以限制人类胆管疾病的衰老依赖性恶化。衰老被认为是引起胆道胆管病的原因，但这是如何调节的尚不清楚。在这里，作者通过删除胆管中的Mdm 2产生了胆管衰老的小鼠模型，并表明抑制TGFβ限制了胆管病的衰老依赖性加重。
Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytes and hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts the transmission of senescence and restores liver function. We identify cellular senescence as a detrimental mechanism in the development of biliary injury. Our results identify TGFβ as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies. Senescence has been suggested as causing biliary cholangiopathies but how this is regulated is unclear. Here, the authors generate a mouse model of biliary senescence by deleting Mdm2 in bile ducts and show that inhibiting TGFβ limits senescence-dependent aggravation of cholangiopathies.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
1.5
作者：
Means, Anna L.;Xu, Yanwen;Gu, Guoqiang
通讯作者：
Gu, Guoqiang
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J