Conditional genetic elimination of hepatocyte growth factor in mice compromises liver regeneration after partial hepatectomy.
Conditional genetic elimination of hepatocyte growth factor in mice compromises liver regeneration after partial hepatectomy.
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DOI：
10.1371/journal.pone.0059836
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Michalopoulos GK
中科院分区：
文献类型：
--
作者：
Nejak-Bowen K;Orr A;Bowen WC Jr;Michalopoulos GK
肝细胞生长因子（HGF）已被证明是肝脏再生不可或缺的，因为它是驱动肝细胞增殖的主要有丝分裂刺激。我们假设，在成年小鼠中切除HGF会对肝细胞再生能力产生负面影响。在缺乏HGF外显子5并携带Mx1-cre或Cre-ERT转基因的小鼠中，通过诱导系统重组实现HGF基因的缺失。治疗10天后对动物肝脏基因组DNA的分析显示，大多数（70-80%）等位基因发生了cree诱导的基因重组。然而，有趣的是，RT-PCR分析显示，在治疗后，未重组和重组形式的HGF mRNA继续存在。将肝细胞群分离为肝细胞和非实质细胞，两种细胞类型的基因组HGF重组相同。即使在肝部分切除（PH）后，肝脏中仍大量存在未重组形式的HGF mRNA，这与HGF蛋白和肝细胞增殖的不显著变化相关。培养的星状细胞产生的HGF的数量与HGF的浓度间接成正比，表明HGF的减少可能诱导残留未重组等位基因的细胞重新合成HGF。四氯化碳（CCl4）诱导的再生导致先前存在的HGF mRNA和蛋白质的大量减少，随后的PH导致再生反应延迟。因此，即使基因重组影响了大多数细胞，HGF mRNA仍然存在于肝脏中；然而，CCl4治疗后的PH与HGF mRNA和蛋白质的减少相关，并导致肝脏再生受损，验证了该有丝分裂原在肝脏生长中的重要作用。
Hepatocyte growth factor (HGF) has been shown to be indispensable for liver regeneration because it serves as a main mitogenic stimulus driving hepatocytes toward proliferation. We hypothesized that ablating HGF in adult mice would have a negative effect on the ability of hepatocytes to regenerate. Deletion of the HGF gene was achieved by inducing systemic recombination in mice lacking exon 5 of HGF and carrying the Mx1-cre or Cre-ERT transgene. Analysis of liver genomic DNA from animals 10 days after treatment showed that a majority (70–80%) of alleles underwent cre-induced genetic recombination. Intriguingly, however, analysis by RT-PCR showed the continued presence of both unrecombined and recombined forms of HGF mRNA after treatment. Separation of liver cell populations into hepatocytes and non-parenchymal cells showed equal recombination of genomic HGF in both cell types. The presence of the unrecombined form of HGF mRNA persisted in the liver in significant amounts even after partial hepatectomy (PH), which correlated with insignificant changes in HGF protein and hepatocyte proliferation. The amount of HGF produced by stellate cells in culture was indirectly proportional to the concentration of HGF, suggesting that a decrease in HGF may induce de novo synthesis of HGF from cells with residual unrecombined alleles. Carbon tetrachloride (CCl4)-induced regeneration resulted in a substantial decrease in preexisting HGF mRNA and protein, and subsequent PH led to a delayed regenerative response. Thus, HGF mRNA persists in the liver even after genetic recombination affecting most cells; however, PH subsequent to CCl4 treatment is associated with a decrease in both HGF mRNA and protein and results in compromised liver regeneration, validating an important role of this mitogen in hepatic growth.
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影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
影响因子：
64.8
作者：
NAKAMURA, T;NISHIZAWA, T;SHIMIZU, S
通讯作者：
SHIMIZU, S
影响因子：
2.8
作者：
Chu, Sheng-Hua;Feng, Dong-Fu;Qiu, Jian-Hua
通讯作者：
Qiu, Jian-Hua
影响因子：
2.9
作者：
OKIGAKI, M;KOMADA, M;KITAMURA, N
通讯作者：
KITAMURA, N
DOI：
10.1016/0006-291x(89)92733-2
发表时间：
1989-12-29
影响因子：
3.1
作者：
KINOSHITA, T;TASHIRO, K;NAKAMURA, T
通讯作者：
NAKAMURA, T