NUPR1 acts as a pro-survival factor in human bone marrow-derived mesenchymal stem cells and is induced by the hypoxia mimetic reagent deferoxamine
NUPR1 acts as a pro-survival factor in human bone marrow-derived mesenchymal stem cells and is induced by the hypoxia mimetic reagent deferoxamine
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DOI：
10.3164/jcbn.18-112
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发表时间：
2019-03
影响因子：
2.4
通讯作者：
K. Matsunaga;K. Fujisawa;T. Takami;G. Burganova;Nanami Sasai;Toshihiko Matsumoto;N. Yamamoto;I. Sakaida
中科院分区：
文献类型：
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作者：
K. Matsunaga;K. Fujisawa;T. Takami;G. Burganova;Nanami Sasai;Toshihiko Matsumoto;N. Yamamoto;I. Sakaida
再生医学中使用的间充质干细胞培养条件的差异可能会影响其分化能力、基因组不稳定性和治疗效果。特别是，已知在缺氧条件下培养的骨髓间充质干细胞在维持未分化状态的同时增殖，并且使用去铁胺（一种模拟缺氧试剂）已被证明是将细胞维持在缺氧代谢状态下的合适策略。在这里，研究了去铁胺在间充质干细胞中的作用，以深入了解调节干细胞存活的机制。 12 小时去铁胺治疗可减少增殖、耗氧量、线粒体活性和 ATP 产生。微阵列分析表明，去铁胺增强了糖酵解和 HIF1α 通路相关基因的转录。在最早的变化中，在 HIF1α、NUPR1 和 EGLN 中观察到转录变异，这与之前的报道一致，表明短期去铁胺治疗会诱导间充质干细胞糖酵解途径发生实质性变化。 NUPR1由应激诱导并参与自噬介导的生存，去铁胺以浓度依赖性方式上调该NUPR1。一致地，发现 NUPR1 敲低可减少细胞增殖并增加星形孢菌素的促凋亡作用，表明去铁胺诱导的 NUPR1 促进间充质干细胞存活和细胞保护性自噬。我们的研究结果可能大大有助于提高基于间充质干细胞的再生医学的有效性。
Differences in the culturing conditions of mesenchymal stem cells used in regenerative medicine may affect their differentiation ability, genome instability, and therapeutic effects. In particular, bone marrow-derived mesenchymal stem cells cultured under hypoxia are known to proliferate while maintaining an undifferentiated state and the use of deferoxamine, a hypoxia mimetic reagent, has proven to be a suitable strategy to maintain the cells under hypoxic metabolic state. Here, the deferoxamine effects were investigated in mesenchymal stem cells to gain insights into the mechanisms regulating stem cell survival. A 12-h deferoxamine treatment reduced proliferation, oxygen consumption, mitochondrial activity, and ATP production. Microarray analysis revealed that deferoxamine enhanced the transcription of genes involved in glycolysis and the HIF1α pathway. Among the earliest changes, transcriptional variations were observed in HIF1α, NUPR1, and EGLN, in line with previous reports showing that short deferoxamine treatments induce substantial changes in mesenchymal stem cells glycolysis pathway. NUPR1, which is induced by stress and involved in autophagy-mediated survival, was upregulated by deferoxamine in a concentration-dependent manner. Consistently, NUPR1 knockdown was found to reduce cell proliferation and increase the proapoptotic effect of staurosporine, suggesting that deferoxamine-induced NUPR1 promotes mesenchymal stem cell survival and cytoprotective autophagy. Our findings may substantially contribute to improve the effectiveness of mesenchymal stem cell-based regenerative medicine.