A cytoprotective role for the heme oxygenase-1/CO pathway during neural differentiation of human mesenchymal stem cells
A cytoprotective role for the heme oxygenase-1/CO pathway during neural differentiation of human mesenchymal stem cells
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DOI：
10.1002/jnr.21660
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发表时间：
2008-07-01
影响因子：
4.2
通讯作者：
Motterlini, Roberto
中科院分区：
文献类型：
--
作者：
Barbagallo, Ignazio;Tibullo, Daniele;Motterlini, Roberto
血红素加氧酶-1（HO-1）是一种诱导性蛋白，它催化血红素氧化为一氧化碳（CO）和胆绿素，在细胞抗氧化应激和调节细胞增殖分化中发挥协同作用。在这里，我们报告说，HO-1的表达和活性可以高度增加未分化的人间充质干细胞（MSC）与氯化血红素，一个已知的HO-1诱导剂处理。然而，HO-1 mRNA和蛋白表达逐渐减少，当MSC在体外进行神经分化，使他们非常容易受到谷氨酸介导的细胞毒性。HO-1的时程显示，该蛋白在2天后显著下调，并在分化后6天恢复到对照水平。与未分化的细胞相比，神经分化2天后用谷氨酸（250 μ M）处理导致更明显的乳酸脱氢酶释放，这是细胞损伤的标志。值得注意的是，用氯化血红素（50 μ M）或释放少量CO的化合物（10 μ M CORM-3和CORM-A1）预处理的细胞使细胞对谷氨酸诱导的毒性更具抵抗力;这种作用在未分化和分化的MSC中都是明显的。我们的研究结果表明，骨髓间充质干细胞在分化的早期阶段通过暂时抑制HO-1表达的机制变得更容易受到氧化损伤。因此，HO-1和CO-释放分子的过表达可以提供一种可能的治疗策略，以提高神经分化过程中的细胞活力，在使用干细胞技术的应用。(C)2008 Wiley-Liss，Inc.
The inducible protein heme oxygenase-1 (HO-1) catalyzes the oxidation of heme to carbon monoxide (CO) and biliverdin, which play a concerted action in cytoprotection against oxidative stress and in the modulation of cell proliferation and differentiation. Here we report that both HO-1 expression and activity can be highly increased in undifferentiated human mesenchymal stem cells (MSCs) treated with hemin, a known HO-1 inducer. However, HO-1 mRNA and protein expression gradually decrease when MSCs undergo neural differentiation in vitro, making them extremely susceptible to glutamate-mediated cytotoxicity. A time course for HO-1 revealed that this protein is markedly down-regulated after 2 days and returns to control levels 6 days after differentiation. Treatment with glutamate (250 mu M) after 2 days of neural differentiation resulted in a more pronounced lactate dehydrogenase release, a marker of cell injury, compared with undifferentiated cells. Notably, cells pretreated with hemin (50 mu M) or compounds that release small amounts of CO (10 mu M CORM-3 and CORM-A1) rendered cells more resistant to glutamate-induced toxicity; this effect was evident in both undifferentiated and differentiated MSCs. Our findings indicate that MSCs become more vulnerable to oxidative injury during the early stages of differentiation via mechanisms that involve a temporary inhibition of HO-1 expression. Thus, overexpression of HO-1 and CO-releasing molecules could provide a possible therapeutic strategy to improve cell viability during neural differentiation in applications that use stem cell technology. (C) 2008 Wiley-Liss, Inc.