Zhao Y, Carroll D W, You Y, Chaiswing L, Wen R, Batinic-Haberle I, Bondada S, Liang Y, St Clair D K
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Department of Neurosurgery, University of Texas, Houston, TX, USA.
Redox Biol. 2017 Aug;12:129-138. doi: 10.1016/j.redox.2017.02.005. Epub 2017 Feb 10.
The signaling of reactive oxygen species (ROS) is essential for the maintenance of normal cellular function. However, whether and how ROS regulate stem cells are unclear. Here, we demonstrate that, in transgenic mice expressing the human manganese superoxide dismutase (MnSOD) gene, a scavenger of ROS in mitochondria, the number and function of mouse hematopoietic stem/progenitor cells (HSPC) under physiological conditions are enhanced. Importantly, giving MnTnBuOE-2-PyP(MnP), a redox- active MnSOD mimetic, to mouse primary bone marrow cells or to C57B/L6 mice significantly enhances the number of HSPCs. Mechanistically, MnP reduces superoxide to hydrogen peroxide, which activates intracellular Nrf2 signaling leading to the induction of antioxidant enzymes, including MnSOD and catalase, and mitochondrial uncoupling protein 3. The results reveal a novel role of ROS signaling in regulating stem cell function, and suggest a possible beneficial effect of MnP in treating pathological bone marrow cell loss and in increasing stem cell population for bone marrow transplantation.
活性氧（ROS）信号传导对于维持正常细胞功能至关重要。然而，ROS是否以及如何调节干细胞尚不清楚。在此，我们证明，在表达人锰超氧化物歧化酶（MnSOD）基因（一种线粒体中ROS的清除剂）的转基因小鼠中，生理条件下小鼠造血干/祖细胞（HSPC）的数量和功能得到增强。重要的是，将氧化还原活性MnSOD模拟物MnTnBuOE-2-PyP（MnP）给予小鼠原代骨髓细胞或C57B/L6小鼠可显著增加HSPC的数量。从机制上讲，MnP将超氧化物还原为过氧化氢，后者激活细胞内Nrf2信号传导，导致包括MnSOD和过氧化氢酶在内的抗氧化酶以及线粒体解偶联蛋白3的诱导。这些结果揭示了ROS信号传导在调节干细胞功能中的新作用，并提示MnP在治疗病理性骨髓细胞丢失和增加骨髓移植干细胞数量方面可能具有有益作用。
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