肝细胞生长因子分泌的间充质干细胞在肝纤维化大鼠模型的

StephenW

Subject Category: Stem cells and regenerative medicine

Citation: Experimental & Molecular Medicine (2014) 46, e110; doi:10.1038/emm.2014.49
Published online 22 August 2014
Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis


Myung-Deok Kim1,2,6, Sung-Soo Kim3,4,6, Hyun-Young Cha1, Seung-Hun Jang1,2, Da-Young Chang3, Wookhwan Kim2,5, Haeyoung Suh-Kim3 and Jae-Ho Lee1,2

    1Department of Biochemistry, Ajou University School of Medicine, Suwon, Republic of Korea
    2Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Republic of Korea
    3Department of Anatomy, Ajou University School of Medicine, Suwon, Republic of Korea
    4Center for Cell Death Regulating Biodrug, Ajou University School of Medicine, Suwon, Republic of Korea
    5Department of General Surgery, Ajou University School of Medicine, Suwon, Republic of Korea

Correspondence: Professor H Suh-Kim, Department of Anatomy, Ajou University School of Medicine, Youngtong-gu, Woncheon-dong, San 5, Suwon 443-749, Republic of Korea. E-mail: [email protected]; Professor J-H Lee, Department of Biochemistry, Ajou University School of Medicine, Yeongtong-gu, Wonchen-dong, San 5, Suwon 443-721, Republic of Korea. E-mail: [email protected]

6These two authors contributed equally to this work.

Received 11 May 2014; Accepted 8 June 2014
Top of page
Abstract

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.

StephenW

主题分类：干细胞和再生医学

引用：实验和分子医学（2014年）46，E110; DOI：10.1038/ emm.2014.49
网上公布的22月到2014年
肝细胞生长因子分泌的间充质干细胞在肝纤维化大鼠模型的治疗效果


李明博德日报Kim1,2,6，宋秀Kim3,4,6，炫扬CHA1，升勋Jang1,2，大安杨长3，Wookhwan Kim2,5，Haeyoung徐-Kim3和宰豪Lee1， 2

    生物化学，亚洲大学医学院，水原，大韩民国教研室
    2Chronic炎症性疾病研究中心，亚洲大学医学院，水原，大韩民国
    解剖学，亚洲大学医学院，水原，韩国的3Department
    4Center细胞死亡调节Biodrug，亚洲大学医学院，水原，大韩民国
    5Department普外科，亚洲大学医学院，水原，韩国的

通讯地址：ħ教授徐，金，解剖学系，亚洲大学医学院，Youngtong区，远川洞，圣5，水原443-749，大韩民国。电子邮箱：[email protected]; JH李教授，生物化学系，亚洲大学医学院，灵通区，Wonchen洞，圣5，水原443-721，韩国。电子邮箱：[email protected]

6These两位作者同等贡献这项工作。

收到2014年5月11日;接受2014年6月8日
返回页首
摘要

骨髓来源的间充质基质细胞（MSCs），已经报道有利于肝纤维化的治疗。这里，我们研究了用遗传工程的MSCs过表达肝细胞生长因子（HGF），以改善肝纤维化的治疗效果的手段。肝纤维化是引起腹腔注射二甲基亚硝胺的。肝细胞生长因子分泌，制备了干细胞转导与腺病毒携带肝细胞生长因子编码基因干细胞（MSCS/ HGF）。干细胞或干细胞/ HGF直接注射到肝纤维化大鼠脾脏。组织纤维化是由组织学分析干细胞注射12天后进行评估。虽然随着干细胞治疗肝纤维化减轻，治疗与干细胞/ HGF产生了更多的显著减少并升高HGF水平在门静脉有关。在肝脏中提取的胶原蛋白水平的MSC/ HGF治疗后明显下降，这表明从纤维化恢复。此外，肝功能中的动物接收的MSC/ HGF得到改善，这表明，MSC / HGF治疗导致不仅在减少肝纤维化，而且在改善肝功能的影响。细胞和生化指标的评估显示，纤维化细胞因子PDGF-BB和TGF-β1mRNA水平的MSC/ HGF治疗后显著下降。随后，以胶原的减少，基质的金属蛋白酶9的表达（MMP-9），MMP-13，MMP-14和尿激酶型纤溶酶原激活剂是增强以下的MSC / HGF，而金属蛋白酶-1（TIMP-1的组织抑制剂）表达减少。最后，治疗用的MSC/ HGF导致了一种改进的治疗效果与单独的MSC HGF的抗纤维化活性的，可能是因为，相比。因此，MSC/代表肝细胞生长因子对细胞治疗肝纤维化的一种很有前途的方法。