Reduced production of laminin by hepatic stellate cells contributes to impairment in oval cell response to liver injury in aged mice
Reduced production of laminin by hepatic stellate cells contributes to impairment in oval cell response to liver injury in aged mice
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肝星状细胞产生层粘连蛋白的减少导致老年小鼠卵圆细胞对肝损伤的反应受损
DOI：
10.18632/aging.101665
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发表时间：
2018
期刊：
影响因子：
5.2
通讯作者：
Zhang Yanyun
中科院分区：
文献类型：
--
作者：
Qian Liu;zhang Hui;Gu Yuting;Li Dechun;Wang Hui;He Sonfbin;Cheng Yiji;Yang Wanlin;Yu Hongshuang;Zhao Xiaonan;Cai Wei;Meng Lijun;Jin Min;Wang Yanan;Zhang Yanyun
老年肝脏通常因肝损伤而受损。组织特异性干细胞参与组织损伤的修复。然而，卵圆细胞(OCs)对损伤的反应以及组织微环境是如何调控这一过程的，目前还不完全清楚。在这项研究中，我们利用成熟的小鼠OC激活模型，证明了老年小鼠在损伤时OCs的激活程度较低，这种损害主要归因于其生态位功能障碍。通过对整体基因表达的分析，我们发现在损伤的幼年和老年小鼠肝组织中差异表达的基因主要是与细胞外基质的形成和重塑有关的基因。层粘连蛋白作为OC小生境中最重要的细胞外基质成分之一，具有促进OCS增殖的作用。不足为奇的是，层粘连蛋白随着年龄的增长而下调。与老年肝星状细胞(HSCs)DNA依赖蛋白激酶(DNA-PK)编码基因的下调一致，抑制DNA-PK也导致HSCs中层粘连蛋白的表达减少。此外，层粘连蛋白可以挽救DNA损伤的HSCs对OC活性的支持减少所致的OC激活障碍。这项研究揭示了在衰老过程中OCS功能受损的一种新的细胞机制。
Aged liver is usually impaired in response to hepatic injury. Tissue-specific stem cells participate in the repair of tissue injury. However, how oval cells (OCs) respond to injury and how the process is regulated by tissue microenvironment in aged mice have not been fully understood. In this study, taking advantage of well-established murine OC activation model, we demonstrated that OCs were less activated upon injury in aged mice and the impairment was mainly attributed to dysfunction in their niche. Through analyzing global gene expression, we found that the genes differentially expressed in damaged young and aged mouse liver tissues were predominantly those required for the formation and remodeling of extracellular matrix. As one of the most important extracellular matrix components in the OC niche, laminin was shown to promote the proliferation of OCs. Not surprisingly, laminin was downregulated with aging. Consistent with the downregulation of genes encoding DNA-dependent protein kinase (DNA-PK) proteins in aged hepatic stellate cells (HSCs), inhibition of DNA-PK also led to reduced expression of laminin in HSCs. Moreover, impairment in OC activation caused by less supporting from DNA-damaged HSCs could be rescued by laminin. This study reveals a new cellular mechanism underlying impaired OCs functionality during aging.