MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK.
MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, EH16 4TJ, UK.
Nat Commun. 2018 Mar 9;9(1):1020. doi: 10.1038/s41467-018-03299-5.
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.
细胞衰老（cellular senescence）是一种提供细胞周期进程不可逆屏障的机制，以防止不必要的增殖。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。我们开发了一种基于 Krt19 启动子控制下胆管中 Mdm2 条件性缺失的胆汁性衰老小鼠模型，该模型表现出胆汁性疾病的特征。在这里，我们报告称，衰老的胆管细胞诱导细胞和信号微环境发生深刻变化，招募肌成纤维细胞和巨噬细胞导致胶原沉积、TGFβ 产生，并诱导周围胆管细胞和肝细胞衰老。最后，我们研究了如何抑制 TGFβ 信号转导破坏衰老的传递并恢复肝功能。我们将细胞衰老确定为胆汁性损伤发展中的一种有害机制。我们的结果表明，TGFβ 是限制人类胆管病中与衰老相关的恶化的潜在治疗靶点。
