Liver-specific ablation of integrin-linked kinase in mice results in abnormal histology, enhanced cell proliferation, and hepatomegaly.
Liver-specific ablation of integrin-linked kinase in mice results in abnormal histology, enhanced cell proliferation, and hepatomegaly.
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DOI：
10.1002/hep.22537
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发表时间：
2008-12
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;Apte, Udayan;Mars, Wendy M.;Bowen, William C.;Luo, Jian-Hua;Yang, Yu;Yu, Yan P.;Orr, Ann;St-Arnaud, Rene;Dedhar, Shoukat;Kaestner, Klaus H.;Wu, Chuanyue;Michalopoulos, George K.
肝细胞的分化和增殖受细胞外基质（ECM）的影响很大。没有基质培养的原代肝细胞随着时间的推移会去分化，但基质覆盖会迅速恢复分化。 ECM 在肝脏再生中也至关重要，其中 ECM 降解和重建是再生过程中的步骤。整合素连接激酶 (ILK) 是一种细胞 ECM 粘附成分，通过整合素参与细胞 ECM 信号传导。我们使用 LoxP/Cre 模型系统研究了 ILK 在整个肝脏中的作用。通过将纯合 ILK floxed 动物与在甲胎蛋白增强子和白蛋白启动子控制下表达 Cre 重组酶的小鼠交配，ILK 从肝脏中消除。 ILK 消融后，动物出生时正常。然而，出生后不久，它们就会出现组织学异常，其特征是肝板紊乱、肝细胞和胆管细胞增殖增加以及细胞外基质沉积增加。细胞增殖伴随着β-连环蛋白的细胞质和核稳定性的增加。所有上皮成分短暂增殖后，增殖消退，ILK 缺陷肝细胞的肝脏最终肝脏与体重的比率是野生型的两倍。细胞增殖阶段基因表达的微阵列分析显示整合素和基质相关基因的上调以及分化相关基因的同时下调。然而，在增殖阶段之后，先前的趋势发生逆转，导致 ILK 缺陷的肝脏出现超分化表型。我们的结果首次在体内证明了 ILK 和肝 ECM 信号传导对肝细胞增殖和分化调节的重要性。
Hepatocyte differentiation and proliferation are greatly affected by extracellular matrix (ECM). Primary hepatocytes cultured without matrix dedifferentiate over time, but matrix overlay quickly restores differentiation. ECM also is critical in liver regeneration where ECM degradation and reconstitution are steps in the regenerative process. Integrin-linked kinase (ILK) is a cell-ECM-adhesion component implicated in cell–ECM signaling by means of integrins. We investigated the role of ILK in whole liver by using the LoxP/Cre model system. ILK was eliminated from the liver by mating homozygous ILK-floxed animals with mice expressing Cre-recombinase under control of the α fetoprotein enhancer and albumin promoter. After ablation of ILK, animals are born normal. Soon after birth, however, they develop histologic abnormalities characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells, and increased deposition of extracellular matrix. Cell proliferation is accompanied by increased cytoplasmic and nuclear stabilization of β-catenin. After this transient proliferation of all epithelial components, proliferation subsides and final liver to body weight ratio in livers with ILK deficient hepatocytes is two times that of wild type. Microarray analysis of gene expression during the stage of cell proliferation shows up-regulation of integrin and matrix-related genes and a concurrent down-regulation of differentiation-related genes. After the proliferative stage, however, the previous trends are reversed resulting in a super-differentiated phenotype in the ILK-deficient livers. Our results show for the first time in vivo the significance of ILK and hepatic ECM-signaling for regulation of hepatocyte proliferation and differentiation.
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DOI：
10.1083/jcb.150.4.861
发表时间：
2000-08-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Huang Y;Li J;Zhang Y;Wu C
通讯作者：
Wu C
影响因子：
5.3
作者：
Einstein, M;Monga, SPS;Deng, CX
通讯作者：
Deng, CX
影响因子：
13.5
作者：
Gkretsi, Vasiliki;Mars, Wendy M.;Michalopoulos, George K.
通讯作者：
Michalopoulos, George K.
影响因子：
3.7
作者：
Kim, TH;Bowen, WC;Michalopoulos, GK
通讯作者：
Michalopoulos, GK
DOI：
10.1073/pnas.060579697
发表时间：
2000-03-28
影响因子：
11.1
作者：
Persad, S;Attwell, S;Dedhar, S
通讯作者：
Dedhar, S