Haider Thomas, Höftberger Romana, Rüger Beate, Mildner Michael, Blumer Roland, Mitterbauer Andreas, Buchacher Tanja, Sherif Camillo, Altmann Patrick, Redl Heinz, Gabriel Christian, Gyöngyösi Mariann, Fischer Michael B, Lubec Gert, Ankersmit Hendrik Jan
University Clinic for Trauma Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria; Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
Exp Neurol. 2015 May;267:230-42. doi: 10.1016/j.expneurol.2015.03.013. Epub 2015 Mar 19.
After spinal cord injury (SCI), secondary damage caused by oxidative stress, inflammation, and ischemia leads to neurological deterioration. In recent years, therapeutic approaches to trauma have focused on modulating this secondary cascade. There is increasing evidence that the success of cell-based SCI therapy is due mainly to secreted factors rather than to cell implantation per se. This study investigated peripheral blood mononuclear cells as a source of factors for secretome- (MNC-secretome-) based therapy. Specifically, we investigated whether MNC-secretome had therapeutic effects in a rat SCI contusion model and its possible underlying mechanisms. Rats treated with MNC-secretome showed substantially improved functional recovery, attenuated cavity formation, and reduced acute axonal injury compared to control animals. Histological evaluation revealed higher vascular density in the spinal cords of treated animals. Immunohistochemistry showed that MNC-secretome treatment increased the recruitment of CD68(+) cells with concomitant reduction of oxidative stress as reflected by lower expression of inducible nitric oxide synthase. Notably, MNC-secretome showed angiogenic properties ex vivo in aortic rings and spinal cord tissue, and experiments showed that the angiogenic potential of MNC-secretome may be regulated by CXCL-1 upregulation in vivo. Moreover, systemic application of MNC-secretome activated the ERK1/2 pathway in the spinal cord. Taken together, these results indicate that factors in MNC-secretome can mitigate the pathophysiological processes of secondary damage after SCI and improve functional outcomes in rats.
脊髓损伤（SCI）后，由氧化应激、炎症和缺血引起的继发性损伤会导致神经功能恶化。近年来，创伤治疗方法主要集中在调节这种继发性级联反应。越来越多的证据表明，基于细胞的SCI治疗的成功主要归因于分泌因子，而非细胞植入本身。本研究将外周血单个核细胞作为基于分泌组（MNC-分泌组）治疗的因子来源进行了调查。具体而言，我们研究了MNC-分泌组在大鼠SCI挫伤模型中是否具有治疗作用及其可能的潜在机制。与对照动物相比，接受MNC-分泌组治疗的大鼠功能恢复显著改善，空洞形成减轻，急性轴突损伤减少。组织学评估显示，治疗动物脊髓中的血管密度更高。免疫组织化学表明，MNC-分泌组治疗增加了CD68(+)细胞的募集，同时氧化应激降低，这表现为诱导型一氧化氮合酶表达降低。值得注意的是，MNC-分泌组在主动脉环和脊髓组织的体外实验中显示出血管生成特性，并且实验表明，MNC-分泌组的血管生成潜力可能在体内由CXCL-1上调调节。此外，MNC-分泌组的全身应用激活了脊髓中的ERK1/2通路。综上所述，这些结果表明，MNC-分泌组中的因子可以减轻SCI后继发性损伤的病理生理过程，并改善大鼠的功能结局。
