Improved Autograft Survival of Mesenchymal Stromal Cells by Plasminogen Activator Inhibitor 1 Inhibition
Improved Autograft Survival of Mesenchymal Stromal Cells by Plasminogen Activator Inhibitor 1 Inhibition
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DOI：
10.1634/stemcells.2008-0520
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发表时间：
2009-01-01
期刊：
影响因子：
5.2
通讯作者：
Galipeau, Jacques
中科院分区：
文献类型：
--
作者：
Copland, Ian B.;Lord-Dufour, Simon;Galipeau, Jacques
间充质基质细胞（MSC）通过其限制细胞凋亡、增强血管生成和指导正性组织重塑的能力显示出强大的修复特性。然而，移植细胞的体内存活率低限制了它们的总体有效性，并显著影响了它们的临床应用。因此，确定改善体内细胞存活的策略是优先事项。对它们存活率低的一种解释是，MSC通常被移植到缺血组织中，例如梗死心肌，那里血液供应差，氧分压低。因此，我们研究了MSC如何应对缺氧，营养不良的应激环境，以确定可以在MSC移植前操纵的营养因子。结合微阵列和蛋白质组学筛选，我们确定纤溶酶原激活物抑制剂1（派-1）作为一个因素一致上调，在我们的体外缺血模拟条件。随后的遗传和化学操作研究将派-1定义为体内MSC存活的负调节因子。从机制上讲，MSC衍生的派-1不会通过纤溶酶依赖性机制改变MSC的存活，而是直接影响MSC向其周围基质的粘附。因此，我们可以得出结论，移植后，派-1通过促进失巢凋亡通过基质分离的MSC的生存产生负面影响。干细胞2009; 27：467-477
Mesenchymal stromal cells (MSCs) display robust reparative properties through their ability to limit apoptosis, enhance angiogenesis, and direct positive tissue remodeling. However, low in vivo survival of transplanted cells limits their overall effectiveness and significantly affects their clinical usage. Consequently, identifying strategies to improve cell survival in vivo are a priority. One explanation for their low survival is that MSCs are often transplanted into ischemic tissue, such as infarcted myocardium, where there is poor blood supply and low oxygen tension. Therefore, we examined how MSCs respond to a hypoxic, nutrient-poor stress environment to identify trophic factors that could be manipulated in advance of MSC transplantation. Combining microarray and proteomic screens we identified plasminogen activator inhibitor 1 (PAI-1) as one factor consistently upregulated in our in vitro ischemia-mimicking conditions. Subsequent genetic and chemical manipulation studies define PAI-1 as a negative regulator of MSC survival in vivo. Mechanistically, MSC-derived PAI-1 does not alter MSC survival through a plasmin-dependent mechanism but rather directly impacts on the adhesiveness of MSCs to their surrounding matrices. Thus we can conclude that post-transplantation, PAI-1 negatively impacts MSC survival by promoting anoikis via matrix detachment. STEM CELLS 2009; 27: 467-477