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Dynamics of neural stem cell-mediated neuroprotection in the presence of oxidative stress: Studies in vitro and in vivo.

机译：存在氧化应激时神经干细胞介导的神经保护的动力学：体内外研究。

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摘要

The interaction of transplanted neural stem cells (NSCs) with the diseased CNS environment can stimulate protection/regeneration of host cells exposed to oxidative stress. To better understand the cellular and molecular principles involved, we first assessed cell survival and levels of reactive oxygen species (ROS) in NSCs and post-mitotic neural progenitors (PNPs) at steady-state and under 3-nitropropionic acid (3-NP)-induced oxidative stress. Subsequently, we studied the interaction between NSCs and their microenvironment in vitro (co-cultures of NSCs and primary striatal cells) and in vivo (NSC-transplanted mice), again under 3-NP insult. In the first segment of our studies, comparing NSCs and the more mature PNPs, we found that NSCs were marked by greater basal mitochondrial activity, lower intracellular ROS levels, and higher expression of key antioxidant enzymes. Further, while 3-NP exposure induced oxidative stress and cell death in PNPs, NSCs survived due to stronger up-regulation of their antioxidant activity. In the second segment of our studies which examined NSC interactions with its microenvironment, both in vitro and in vivo, the presence of NSCs before intoxication decreased free radical production and improved cell survival. In the grafted animals, this resulted in reduced behavioral symptoms, less vascular damage, and prevention of striatal cell loss in comparison to vehicle-injected controls. Intriguingly, during this process of neuroprotection, NSCs were found to rely in their "protective" function on the assistance of bystander cells like the primary or host glial and endothelial cells. Only the resulting network of NSCs, astrocytes, and endothelial cells allowed an up-regulation and secretion of neuroprotective factors high enough to induce antioxidant defense mechanisms that could create the necessary milieu for the observed neuroprotection. In summary, the present dissertation identifies two important characteristics of NSCs not understood before, namely (1) their innate alertness to oxidative stress, and (2) their ability to interact with and induce plastic responses from host cells. These NSC properties, allows them to not only survive in a hostile CNS environment, but also empowers them to protect the host from the arriving impact of oxidative stress.
机译：移植的神经干细胞（NSC）与患病的CNS环境的相互作用可以刺激暴露于氧化应激的宿主细胞的保护/再生。为了更好地理解所涉及的细胞和分子原理，我们首先评估了处于稳态且在3-硝基丙酸（3-NP）下的NSC和有丝分裂后神经祖细胞（PNP）中的细胞存活率和活性氧水平（ROS）。诱导的氧化应激。随后，我们再次在3-NP损伤下研究了NSC及其微环境在体外（NSC与原代纹状体细胞的共培养物）和体内（NSC移植的小鼠）之间的相互作用。在我们的研究的第一部分中，通过比较NSC和更成熟的PNP，我们发现NSC的特征在于更高的基础线粒体活性，更低的细胞内ROS水平以及关键抗氧化酶的更高表达。此外，尽管3-NP暴露会引起PNP中的氧化应激和细胞死亡，但NSC由于其抗氧化剂活性的上调而得以幸存。在我们研究的第二部分中，在体外和体内研究了NSC与微环境的相互作用，中毒前NSC的存在降低了自由基的产生并提高了细胞存活率。与运载体注射的对照相比，在移植的动物中，这可以减少行为症状，减少血管损伤，并防止纹状体细胞丢失。有趣的是，在神经保护的这一过程中，发现神经干细胞依赖于旁观者细胞（如原代或宿主神经胶质和内皮细胞）的“保护”功能。只有所得的NSC，星形胶质细胞和内皮细胞网络才能上调和分泌足够高的神经保护因子，以诱导抗氧化防御机制，从而为观察到的神经保护创造必要的环境。总而言之，本论文确定了NSC的两个重要特征，即以前不了解的，即（1）它们对氧化应激的先天警觉性；（2）它们与宿主细胞相互作用并诱导其塑性反应的能力。这些NSC特性不仅使它们能够在恶劣的CNS环境中生存，而且还使它们能够保护宿主免受氧化应激的影响。

著录项

  • 作者

    Madhavan, Lalitha.;

  • 作者单位

    Iowa State University.;

  • 授予单位 Iowa State University.;
  • 学科 Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 144 p.
  • 总页数 144
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;
  • 关键词

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