Loss of integrin linked kinase from mouse hepatocytes in vitro and in vivo results in apoptosis and hepatitis
Loss of integrin linked kinase from mouse hepatocytes in vitro and in vivo results in apoptosis and hepatitis
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DOI：
10.1002/hep.21540
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发表时间：
2007-04-01
期刊：
影响因子：
13.5
通讯作者：
Michalopoulos, George K.
中科院分区：
文献类型：
--
作者：
Gkretsi, Vasiliki;Mars, Wendy M.;Michalopoulos, George K.
细胞外基质（ECM）是组织内细胞存活的基础。失去与周围ECM的接触通常会导致细胞分化改变或细胞死亡。无基质培养的肝细胞失去了肝细胞特异性基因表达模式和特征性细胞微结构。然而，向去分化肝细胞中加入水合基质制剂后，分化恢复。整合素连接激酶（ILK）是细胞-ECM粘附的重要组分，其将整合素信号传导至细胞内部。ILK与许多基本的细胞过程如分化、增殖和存活有关。在这项研究中，我们研究了ILK在体外和体内小鼠肝细胞中的作用。从原代小鼠肝细胞中消耗ILK导致细胞凋亡增强。这伴随着半胱天冬酶3活性的增加和PINCH和α-parvin表达的显著降低，PINCH和α-parvin与ILK沿着在细胞-ECM粘附处形成稳定的充分表征的三元复合物。由ILK耗竭引起的细胞凋亡的诱导可以通过ILK的同时过表达而基本上逆转，表明细胞凋亡确实是ILK去除的结果。这些结果通过体内数据进一步证实，体内数据显示通过尾静脉注射在ILK-固定的动物中腺病毒递送Cre-重组酶导致急性肝炎，具有多种病理学发现，包括炎症、脂肪变化和细胞凋亡、异常有丝分裂、水肿变性和坏死。结论：我们的研究结果表明，ILK和整合素信号转导的肝细胞的存活和维持正常的肝功能的重要性。
Extracellular matrix (ECM) is fundamental for the survival of cells within a tissue. Loss of contact with the surrounding ECM often causes altered cell differentiation or cell death. Hepatocytes cultured without matrix lose patterns of hepatocyte-specific gene expression and characteristic cellular micro-architecture. However, differentiation is restored after the addition of hydrated matrix preparations to dedifferentiated hepatocytes. Integrin-linked kinase (ILK) is an important component of cell-ECM adhesions transmitting integrin signaling to the interior of the cell. ILK has been implicated in many fundamental cellular processes such as differentiation, proliferation, and survival. In this study, we investigated the role of ILK in mouse hepatocytes in vitro as well as in vivo. Depletion of ILK from primary mouse hepatocytes resulted in enhanced apoptosis. This was accompanied by increased caspase 3 activity and a significant decrease in expression of PINCH and alpha-parvin, which, along with ILK, form a stable well-characterized ternary complex at cell-ECM adhesions. The induction of apoptosis caused by ILK depletion could be substantially reversed by simultaneous overexpression of ILK, indicating that apoptosis is indeed a consequence of ILK removal. These results were further corroborated via in vivo data showing that adenoviral delivery of Cre-recombinase in ILK-floxed animals by tail vein injection resulted in acute hepatitis, with a variety of pathological findings including inflammation, fatty change, and apoptosis, abnormal mitoses, hydropic degeneration, and necrosis. Conclusion: Our results demonstrate the importance of ILK and integrin signaling for the survival of hepatocytes and the maintenance of normal liver function.