Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis.
Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis.
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DOI：
10.1038/emm.2014.49
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发表时间：
2014-08-22
影响因子：
12.8
通讯作者：
Lee, Jae-Ho
中科院分区：
文献类型：
--
作者：
Kim, Myung-Deok;Kim, Sung-Soo;Cha, Hyun-Young;Jang, Seung-Hun;Chang, Da-Young;Kim, Wookhwan;Suh-Kim, Haeyoung;Lee, Jae-Ho
骨髓间充质干细胞（MSCs）已被报道用于治疗肝纤维化。在这里，我们研究了使用基因工程MSC，过表达肝细胞生长因子（HGF）作为一种手段，以提高其在肝纤维化的治疗效果。腹腔注射二甲基亚硝胺诱导肝纤维化。通过用携带HGF编码cDNA的腺病毒转导MSC来制备分泌HGF的MSC（MSC/HGF）。将MSCs或MSCs/HGF直接注射到纤维化大鼠的脾脏中。在干细胞注射后12天通过组织学分析评估组织纤维化。虽然用MSC治疗减少了纤维化，但用MSC/HGF治疗产生了更显著的减少，并且与门静脉中HGF水平升高相关。肝提取物中的胶原蛋白水平在MSC/HGF治疗后降低，表明从纤维化中恢复。此外，接受MSC/HGF的动物的肝功能得到改善，表明MSC/HGF治疗不仅减少了肝纤维化，而且改善了肝细胞功能。细胞和生化参数的评估显示，MSC/HGF治疗后，纤维化细胞因子PDGF-bb和TGF-β1的mRNA水平显著降低。继胶原减少后，基质金属蛋白酶-9（MMP-9）、MMP-13、MMP-14和尿激酶型纤溶酶原激活物的表达在MSC/HGF后增加，而金属蛋白酶组织抑制剂-1（TIMP-1）的表达减少。总之，与单独的MSC相比，MSC/HGF治疗导致治疗效果改善，这可能是因为HGF的抗纤维化活性。因此，MSC/HGF代表了一种有前途的肝纤维化细胞治疗方法。
Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to be beneficial for the treatment of liver fibrosis. Here, we investigated the use of genetically engineered MSCs that overexpress hepatocyte growth factor (HGF) as a means to improve their therapeutic effect in liver fibrosis. Liver fibrosis was induced by intraperitoneal injection of dimethylnitrosamine. HGF-secreting MSCs (MSCs/HGF) were prepared by transducing MSCs with an adenovirus carrying HGF-encoding cDNA. MSCs or MSCs/HGF were injected directly into the spleen of fibrotic rats. Tissue fibrosis was assessed by histological analysis 12 days after stem cell injection. Although treatment with MSCs reduced fibrosis, treatment with MSCs/HGF produced a more significant reduction and was associated with elevated HGF levels in the portal vein. Collagen levels in the liver extract were decreased after MSC/HGF therapy, suggesting recovery from fibrosis. Furthermore, liver function was improved in animals receiving MSCs/HGF, indicating that MSC/HGF therapy resulted not only in reduction of liver fibrosis but also in improvement of hepatocyte function. Assessment of cell and biochemical parameters revealed that mRNA levels of the fibrogenic cytokines PDGF-bb and TGF-β1 were significantly decreased after MSC/HGF therapy. Subsequent to the decrease in collagen, expression of matrix metalloprotease-9 (MMP-9), MMP-13, MMP-14 and urokinase-type plasminogen activator was augmented following MSC/HGF, whereas tissue inhibitor of metalloprotease-1 (TIMP-1) expression was reduced. In conclusion, therapy with MSCs/HGF resulted in an improved therapeutic effect compared with MSCs alone, probably because of the anti-fibrotic activity of HGF. Thus, MSC/HGF represents a promising approach toward a cell therapy for liver fibrosis.
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影响因子：
5.2
作者：
Carvalho, Adriana B.;Quintanilha, Lutz Fernando;Goldenberg, Regina C. S.
通讯作者：
Goldenberg, Regina C. S.
DOI：
10.1111/j.1440-1746.2006.04708.x
发表时间：
2007-11-01
影响因子：
4.1
作者：
Asawa, Sadanori;Saito, Takuro;Gotoh, Mitsukazu
通讯作者：
Gotoh, Mitsukazu
影响因子：
5.2
作者：
Kim, Sung-Soo;Yoo, Seung-Wan;Suh-Kim, Haeyoung
通讯作者：
Suh-Kim, Haeyoung
影响因子：
6
作者：
Kim, WH;Matsumoto, K;Nakamura, T
通讯作者：
Nakamura, T
影响因子：
20.3
作者：
Aggarwal, S;Pittenger, MF
通讯作者：
Pittenger, MF