Lysophosphatidic acid protects mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis
Lysophosphatidic acid protects mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis
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DOI：
10.1634/stemcells.2007-0098
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发表时间：
2008-01-01
期刊：
影响因子：
5.2
通讯作者：
Chen, Xi
中科院分区：
文献类型：
--
作者：
Chen, Jinghai;Baydoun, Anwar R.;Chen, Xi
骨髓间充质干细胞（MSC）在心脏修复方面显示出巨大的前景。然而，移植的间充质干细胞在缺血心脏内的生存能力较差，限制了其治疗潜力。我们之前的研究已经证明，缺氧和血清剥夺（缺氧/SD）通过线粒体凋亡途径诱导MSCs凋亡。由于已知急性心肌梗塞后血清溶血磷脂酸 (LPA) 水平显着升高，并且 LPA 增强其他细胞系统的存活，因此我们开始确定 LPA 是否可以保护 MSC 免受缺氧/SD 诱导的细胞凋亡。我们还研究了可能介导 LPA 此类行为的潜在机制。所有实验均在大鼠骨髓 MSC 上进行。通过将细胞暴露于密封的 GENbox 缺氧室中的缺氧/SD 来诱导细胞凋亡。在存在和不存在针对 G(i) 蛋白、丝裂原激活蛋白激酶 ERK1/2 或磷酸肌醇 3 激酶 (PI3K) 的抑制剂的情况下，研究了 LPA 的作用。获得的数据表明，LPA 通过与并行起作用的下游 ERK1/2 和 PI3K/Akt 信号通路相连的 Gi 偶联 LPA(1) 受体，显着减弱缺氧/SD 诱导的细胞凋亡。其他研究表明，LPA 治疗实际上消除了缺氧/SD 诱导的线粒体功能障碍激活，并且 LPA(1) 受体、Gi 蛋白、PI3K/Akt 通路或 ERK 的抑制有效逆转了 LPA 的这种保护作用。综上所述，我们的研究结果表明，LPA 是 MSC 的一种新型、有效的生存因子，这可能被证明对于在梗塞心肌中利用基于 MSC 的疗法具有相当大的治疗意义。
Bone marrow-derived mesenchymal stem cells (MSCs) have shown great promise for cardiac repair. However, poor viability of transplanted MSCs within the ischemic heart has limited their therapeutic potential. Our previous studies have documented that hypoxia and serum deprivation (hypoxia/SD), induced MSCs apoptosis through the mitochondrial apoptotic pathway. Since serum lysophosphatidic acid (LPA) levels are known to be significantly elevated after acute myocardial infarction and that LPA enhanced survival of other cell systems, we embarked on determining whether LPA protects MSCs against hypoxia/SD-induced apoptosis. We have also investigated the potential mechanism(s) that may mediate such actions of LPA. All experiments were carried out on rat bone marrow MSCs. Apoptosis was induced by exposure of cells to hypoxia/SD in a sealed GENbox hypoxic chamber. Effects of LPA were investigated in the absence and presence of inhibitors that target either G(i)proteins, the mitogen activated protein kinases ERK1/2, or phosphoinositide 3-kinase (PI3K). The data obtained showed that hypoxia/SD-induced apoptosis was significantly attenuated by LPA through Gi-coupled LPA(1) receptors linked to the downstream ERK1/2 and PI3K/Akt signaling pathways that function in parallel. Additional studies have demonstrated that hypoxia/SD-induced activation of mitochondrial dysfunction was virtually abolished by LPA treatment and that inhibition of the LPA(1) receptor, Gi proteins, the PI3K/Akt pathway, or ERKs effectively reversed this protective action of LPA. Taken together, our findings indicate that LPA is a novel, potent survival factor for MSCs and this may prove to be of considerable therapeutic significance in terms of exploiting MSC-based therapy in the infracted myocardium.