Stanniocalcin-1 Rescued Photoreceptor Degeneration in Two Rat Models of Inherited Retinal Degeneration
Stanniocalcin-1 Rescued Photoreceptor Degeneration in Two Rat Models of Inherited Retinal Degeneration
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DOI：
10.1038/mt.2011.308
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发表时间：
2012-04-01
影响因子：
12.4
通讯作者：
Prockop, Darwin J.
中科院分区：
文献类型：
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作者：
Roddy, Gavin W.;Rosa, Robert H., Jr.;Prockop, Darwin J.
氧化应激和光感受器凋亡是多种形式的视网膜变性（RD）的突出特征，目前尚无有效的治疗方法。我们之前观察到，间充质干细胞/基质细胞通过被激活分泌斯钙素-1（STC-1）来减少细胞凋亡，斯钙素-1是一种多功能蛋白，可通过上调线粒体解偶联蛋白-2（UCP-2）来减少氧化应激。因此，我们测试了玻璃体内注射STC-1可以挽救光感受器的假设。我们首先在以光感受器快速丧失为特征的视紫红质转基因大鼠中测试了 STC-1。玻璃体内的 STC-1 减少了光感受器核和转录物的损失，并导致可测量的视网膜功能，而在这种快速退化中则没有其他功能。然后，我们在皇家外科学院 (RCS) 大鼠中测试了 STC-1，其特征是光感受器退化较慢。玻璃体内STC-1减少了光感受器中固缩核的数量，延迟了光感受器转录物的损失，并改善了视杆细胞的功能。此外，STC-1 上调 UCP-2 并降低活性氧 (ROS) 产生的两种蛋白质加合物的水平。两个模型的微阵列表明，STC-1 上调了视网膜发育和功能相似基因的表达。结果表明，玻璃体内注射 STC-1 是治疗各种形式的 RD 的一种有前景的疗法，包括色素性视网膜炎和萎缩性年龄相关性黄斑变性 (AMD)。
Oxidative stress and photoreceptor apoptosis are prominent features of many forms of retinal degeneration (RD) for which there are currently no effective therapies. We previously observed that mesenchymal stem/stromal cells reduce apoptosis by being activated to secrete stanniocalcin-1 (STC-1), a multifunctional protein that reduces oxidative stress by upregulating mitochondrial uncoupling protein-2 (UCP-2). Therefore, we tested the hypothesis that intravitreal injection of STC-1 can rescue photoreceptors. We first tested STC-1 in the rhodopsin transgenic rat characterized by rapid photoreceptor loss. Intravitreal STC-1 decreased the loss of photoreceptor nuclei and transcripts and resulted in measurable retinal function when none is otherwise present in this rapid degeneration. We then tested STC-1 in the Royal College of Surgeons (RCS) rat characterized by a slower photoreceptor degeneration. Intravitreal STC-1 reduced the number of pyknotic nuclei in photoreceptors, delayed the loss of photoreceptor transcripts, and improved function of rod photoreceptors. Additionally, STC-1 upregulated UCP-2 and decreased levels of two protein adducts generated by reactive oxygen species (ROS). Microarrays from the two models demonstrated that STC-1 upregulated expression of a similar profile of genes for retinal development and function. The results suggested that intravitreal STC-1 is a promising therapy for various forms of RD including retinitis pigmentosa and atrophic age-related macular degeneration (AMD).