Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis
Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis
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人脐带间充质干细胞衍生的外泌体可缓解肝纤维化
DOI：
10.1089/scd.2012.0395
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发表时间：
2013-03-01
影响因子：
4
通讯作者：
Xu, Wenrong
中科院分区：
文献类型：
--
作者：
Li, Tingfen;Yan, Yongmin;Xu, Wenrong
骨髓间充质干细胞（Mesenchymal stem cells，MSCs）已被认为是一种有吸引力的疾病治疗工具。骨髓间充质干细胞分泌的Exosomes可减轻心肌缺血/再灌注损伤，保护急性肾小管损伤。然而，MSC来源的exosomes是否可以减轻肝纤维化及其机制尚不清楚。先前的工作表明，将人脐带间充质干细胞（hucMSCs）移植到急性损伤和纤维化的肝脏中可以恢复肝功能并改善肝纤维化。在这项研究中，发现移植来源于hucMSC的外来体（hucMSC-Ex）减少了表面纤维囊并使其质地柔软，减轻了四氯化碳（CCl 4）诱导的纤维化肝脏中的肝脏炎症和胶原沉积。hucMSC-Ex还显著恢复了血清天冬氨酸氨基转移酶（AST）活性，降低了I型和III型胶原蛋白、转化生长因子（TGF）-β 1和体内磷酸化Smad 2表达。在进一步的实验中，我们发现hucMSC-Ex移植后上皮-间质转化（EMT）相关标志物E-钙粘蛋白阳性细胞增加，N-钙粘蛋白和波形蛋白阳性细胞减少。此外，人肝细胞系HL 7702在用重组人TGF-β 1诱导后经历典型的EMT，然后hucMSC-Ex处理逆转了体外纺锤形和EMT相关标志物表达。总之，这些结果表明，hucMSC-Ex可以通过抑制EMT和保护肝细胞来改善CCl 4诱导的肝纤维化。这为纤维化肝病的治疗提供了一种新的方法。
Mesenchymal stem cells (MSCs) have been considered as an attractive tool for the therapy of diseases. Exosomes excreted from MSCs can reduce myocardial ischemia/reperfusion damage and protect against acute tubular injury. However, whether MSC-derived exosomes can relieve liver fibrosis and its mechanism remain unknown. Previous work showed that human umbilical cord-MSCs (hucMSCs) transplanted into acutely injured and fibrotic livers could restore liver function and improve liver fibrosis. In this study, it was found that transplantation of exosomes derived from hucMSC (hucMSC-Ex) reduced the surface fibrous capsules and got their textures soft, alleviated hepatic inflammation and collagen deposition in carbon tetrachloride (CCl4)-induced fibrotic liver. hucMSC-Ex also significantly recovered serum aspartate aminotransferase (AST) activity, decreased collagen type I and III, transforming growth factor (TGF)-beta 1 and phosphorylation Smad2 expression in vivo. In further experiments, we found that epithelial-to-mesenchymal transition (EMT)-associated markers E-cadherin-positive cells increased and N-cadherin- and vimentin-positive cells decreased after hucMSC-Ex transplantation. Furthermore, the human liver cell line HL7702 underwent typical EMT after induction with recombinant human TGF-beta 1, and then hucMSC-Ex treatment reversed spindle-shaped and EMT-associated markers expression in vitro. Taken together, these results suggest that hucMSC-Ex could ameliorate CCl4-induced liver fibrosis by inhibiting EMT and protecting hepatocytes. This provides a novel approach for the treatment of fibrotic liver disease.