Exosomes Derived from TIMP2-Modified Human Umbilical Cord Mesenchymal Stem Cells Enhance the Repair Effect in Rat Model with Myocardial Infarction Possibly by the Akt/Sfrp2 Pathway
Exosomes Derived from TIMP2-Modified Human Umbilical Cord Mesenchymal Stem Cells Enhance the Repair Effect in Rat Model with Myocardial Infarction Possibly by the Akt/Sfrp2 Pathway
复制标题
TIMP2 修饰的人脐带间充质干细胞衍生的外泌体可能通过 Akt/Sfrp2 途径增强心肌梗死大鼠模型的修复效果
DOI：
10.1155/2019/1958941
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发表时间：
2019-01-01
影响因子：
--
通讯作者：
Liu, Zheng
中科院分区：
文献类型：
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作者：
Ni, Jing;Liu, Xijun;Liu, Zheng
来源于人脐带间充质干细胞（hucMSCs）的外泌体是心肌梗死（MI）的一种有前途的新治疗选择。组织基质金属蛋白酶抑制剂2，也称为TIMP 2，是金属蛋白酶组织抑制剂家族的成员。由于TIMP 2介导的基质金属蛋白酶（MMPs）抑制是MI后重塑的关键决定因素，我们分析了来自TIMP 2过表达hucMSCs（huc-exoTIMP 2）的外泌体对MI大鼠模型的治疗作用。huc-exoTIMP 2显著改善了体内心脏功能，如通过超声心动图测量的，并促进了MI损伤中的血管生成。它还限制了细胞外基质（ECM）重塑，如减少的胶原沉积所示。此外，huc-exoTIMP 2给药增加了抗凋亡Bcl-2的原位表达，并减少了促凋亡Bax和caspase-9的原位表达。同时，huc-exoTIMP 2上调超氧化物歧化酶（SOD）和谷胱甘肽（GSH），降低丙二醛（MDA）水平在MI模型。huc-exoTIMP 2预处理可抑制H2 O2介导的H9 C2-心肌细胞凋亡，促进人脐静脉内皮细胞（HUVEC）增殖、迁移和管腔形成，并减少TGFβ诱导的心肌成纤维细胞（CFs）分泌MMP 2、MMP 9和α-SMA。此外，huc-exoTIMP 2预处理还可增加梗死心肌Akt磷酸化的表达，这可能与huc-exoTIMP 2中高水平分泌的卷曲相关蛋白2（Sfrp 2）有关，提示其作用机制。重要的是，huc-exoTIMP 2中的Sfrp 2敲低消除了保护作用。总之，huc-exoTIMP 2通过减轻MI诱导的氧化应激和ECM重塑改善心脏功能，部分通过Akt/Sfrp 2途径。
Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) are a promising new therapeutic option for myocardial infarction (MI). The tissue matrix metalloproteinase inhibitor 2, also known as TIMP2, is a member of the tissue inhibitor family of metalloproteinases. Since TIMP2-mediated inhibition of matrix metalloproteinases (MMPs) is a key determinant of post-MI remodeling, we analyzed the therapeutic effects of exosomes derived from TIMP2-overexpressing hucMSCs (huc-exoTIMP2) on the MI rat model. The huc-exoTIMP2 significantly improved in vivo cardiac function as measured by echocardiography and promoted angiogenesis in MI injury. It also restricted extracellular matrix (ECM) remodeling, as indicated by the reduced collagen deposition. In addition, huc-exoTIMP2 administration increased the in situ expression of the antiapoptotic Bcl-2 and decreased that of the proapoptotic Bax and pro-caspase-9 in the infracted myocardium. Meanwhile, huc-exoTIMP2 upregulated superoxide dismutase (SOD) as well as glutathione (GSH) and decreased the malondialdehyde (MDA) level in MI models. In vitro huc-exoTIMP2 pretreatment could inhibit H2O2-mediated H9C2-cardiomyocyte apoptosis and promote human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation, as well as decrease TGFβ-induced MMP2, MMP9, and α-SMA secretion by cardiac fibroblasts (CFs). Besides that, huc-exoTIMP2 pretreatment also increased the expression of Akt phosphorylation in the infarcted myocardium, which may relate to a high level of secreted frizzled-related protein 2 (Sfrp2) in huc-exoTIMP2, indicating a mechanistic basis of its action. Importantly, Sfrp2 knockdown in huc-exoTIMP2 abrogated the protective effects. Taken together, huc-exoTIMP2 improved cardiac function by alleviating MI-induced oxidative stress and ECM remodeling, partly via the Akt/Sfrp2 pathway.