Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney
Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney
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DOI：
10.1634/stemcells.2007-1000
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发表时间：
2008-01-01
期刊：
影响因子：
5.2
通讯作者：
Cussac, Daniel
中科院分区：
文献类型：
--
作者：
Mias, Celine;Trouche, Elodie;Cussac, Daniel
骨髓间充质干细胞（MSCs）在实体器官的细胞治疗中显示出巨大的潜力。提高移植的MSC存活和分泌旁分泌因子的能力的方法代表了这种新疗法进一步发展的挑战之一。在本研究中，我们设计了一种策略，离体预处理与松果体激素褪黑激素，以提高生存，旁分泌活动，和效率的MSC。使用大鼠急性肾功能衰竭模型，我们发现褪黑激素预处理强烈增加骨髓间充质干细胞的存活后，实质内注射。这种作用伴随着过度刺激血管生成、肾细胞增殖和加速肾功能恢复。为了深入了解在体内观察到的作用中涉及的机制，在体外对培养的MSC测试褪黑激素。我们的研究结果表明，通过刺激特定的褪黑激素受体，褪黑激素诱导过氧化氢酶和超氧化物歧化酶-1的过表达，并增加了间充质干细胞对过氧化氢依赖性细胞凋亡的抵抗力。与未处理的细胞相比，褪黑激素孵育的MSC显示出更高的碱性成纤维细胞生长因子和肝细胞生长因子的表达。此外，条件培养基从褪黑激素处理的骨髓间充质干细胞刺激管形成的内皮祖细胞和近端小管细胞的增殖培养。总之，我们的研究结果表明，褪黑激素的行为作为预处理剂增加生存，旁分泌活动，和效率的间充质干细胞。使用这种分子预处理干细胞可能代表了一种新的和安全的方法，以提高实体器官的细胞治疗的有益效果。
Bone marrow mesenchymal stem cells (MSCs) have shown great potential in cell therapy of solid organs. Approaches to improving the ability of grafted MSCs to survive and secrete paracrine factors represent one of the challenges for the further development of this novel therapy. In the present study, we designed a strategy of ex vivo pretreatment with the pineal hormone melatonin to improve survival, paracrine activity, and efficiency of MSCs. Using a rat model of acute renal failure, we showed that melatonin pretreatment strongly increased survival of MSCs after intraparenchymal injection. This effect was concomitant with overstimulation of angiogenesis, proliferation of renal cells, and accelerated recovery of renal function. To gain insight into the mechanisms involved in the effects observed in vivo, melatonin was tested in vitro on cultured MSCs. Our results show that through stimulation of specific melatonin receptors, melatonin induced an overexpression of the antioxidant enzyme catalase and superoxide dismutase-1 and increased the resistance of MSCs to hydrogen peroxide-dependent apoptosis. Compared with untreated cells, MSCs incubated with melatonin displayed a higher expression of basic fibroblast growth factor and hepatocyte growth factor. In addition, conditioned culture media from melatonin-treated MSCs stimulated tube formation by endothelial progenitor cells and proliferation of proximal tubule cells in culture. In conclusion, our results show that melatonin behaves as a preconditioning agent increasing survival, paracrine activity, and efficiency of MSCs. The use of this molecule for pretreatment of stem cells may represent a novel and safe approach to improving the beneficial effects of cell therapy of solid organs.