Mesenchymal Stem Cells Overexpressing CXCR4 Attenuate Remodeling of Postmyocardial Infarction by Releasing Matrix Metalloproteinase-9
Mesenchymal Stem Cells Overexpressing CXCR4 Attenuate Remodeling of Postmyocardial Infarction by Releasing Matrix Metalloproteinase-9
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DOI：
10.1089/scd.2011.0126
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发表时间：
2012-03-01
影响因子：
4
通讯作者：
Wang, Yigang
中科院分区：
文献类型：
--
作者：
Huang, Wei;Wang, Tao;Wang, Yigang
心肌梗死（MI）导致心脏缺血区的肌纤维损失，随后形成瘢痕。这些因素增加了间充质干细胞（MSC）动员的障碍，从而阻碍了它们在心脏修复中的有效性。本研究检测了过表达CXCR 4（MSCCX 4）的MSC通过释放胶原降解酶、基质金属蛋白酶-9（MMP-9）来确定对梗死心肌的渗透。在体外，使用小鼠MSC，包括使用腺病毒转导的MSC，以表达CXCR 4/绿色荧光蛋白（GFP）（MSCCX 4）、GFP/GFP（MSCXR）、用靶向CXCR 4的siRNA处理的MSC（MSCsiR）、用对照siRNA处理的MSC（MSCsiR）。（MSCCon-siR），用靶向MMP-9的siRNA处理的MSCCX 4在一些实施方案中，MSC是来自MMP-14（MSCCX 4-siRMP 9）和MMP-14（MSCCX 4-siRMP 14）的MSC，来源于用腺病毒转导GFP的MMP-9敲除小鼠的MSC（MSCMP 9-），或过表达CXCR 4的MSCMP 9- plus（MSCMP 9-CX4）。使用反式胶原凝胶侵袭试验评估所有MSC穿过基底膜的能力。Western blot检测CXCR 4和MMP的表达。在体内，在MI后7天通过尾静脉注射将具有各种处理的MSC输注到小鼠中。在MSC注射后4周，在收获心脏进行分析之前进行超声心动图。体外和体内研究均表明，与对照组相比，MSCCX 4诱导MMP-9上调，促进GFP（+）细胞迁移到梗死区域。这种增强的反应与左心室（LV）纤维化减少、LV游离壁厚度增加、血管生成和LV功能改善相关。在缺氧条件下，MMP-9在MSCCX 4中上调，从而促进基底膜的穿过，导致MI后组织的重塑改善。
Myocardial infarction (MI) results in loss of myofibers in the ischemic zone of the heart, followed by scar formation. These factors increase barriers to mobilization of mesenchymal stem cells (MSC), thereby impeding their effectiveness in cardiac repair. This study examined MSC overexpressing CXCR4 (MSCCX4) to determine penetration into infarcted myocardium by releasing collagen degrading enzyme, matrix metalloproteinase-9 (MMP-9). In vitro, mouse MSC were utilized, including MSC using adenoviral transduction, to express CXCR4/green fluorescent protein (GFP) (MSCCX4), Null/GFP (MSCNull), MSC treated with siRNA targeting CXCR4 (MSCsiR), MSC treated with control siRNA(MSCCon-siR), MSCCX4 treated with siRNA targeting MMP-9 (MSCCX4-siRMP9) and MMP-14 (MSCCX4-siRMP14), MSC derived from MMP-9 knockout mouse with adenoviral transduction for GFP (MSCMP9-), or MSCMP9- plus overexpressing CXCR4 (MSCMP9-CX4). The ability to cross the basement membrane was evaluated in all MSC using a trans-collagen gel invasion assay. The CXCR4 and MMP expression were analyzed by Western blot. In vivo, MSC with various treatments were infused into mice via tail vein injections 7 days after MI. Echocardiography was performed before harvesting hearts for analysis at 4 weeks after MSC injection. Both in vitro and in vivo studies demonstrated upregulation of MMP-9 induced by MSCCX4, promoting increased GFP(+) cell migration into the infarcted area in comparison to control group. This enhanced response was associated with reduced left ventricular (LV) fibrosis, increased LV free wall thickness, angiogenesis, and improved LV function. Under hypoxic conditions, MMP-9 is upregulated in MSCCX4, thus facilitating cross of the basement membrane, resulting in an improved remodeling of post-MI tissue.