Intrathecal delivery of mesenchymal stromal cells protects the structure of altered perineuronal nets in SOD1 rats and amends the course of ALS.
Intrathecal delivery of mesenchymal stromal cells protects the structure of altered perineuronal nets in SOD1 rats and amends the course of ALS.
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DOI：
10.1002/stem.1812
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发表时间：
2014-12
期刊：
影响因子：
5.2
通讯作者：
Sykova, Eva
中科院分区：
文献类型：
--
作者：
Forostyak, Serhiy;Homola, Ales;Turnovcova, Karolina;Svitil, Pavel;Jendelova, Pavla;Sykova, Eva
肌萎缩性侧索硬化症（ALS）是一种进行性神经退行性疾病，导致致命的结果。我们研究了超氧化物歧化酶1 （SOD1）大鼠在正常病程和人骨髓间充质基质细胞（MSCs）鞘内应用（5 × 105个细胞）后症状表现的腹侧角神经周围网（PNNs）的变化。我们发现MSCs改善了疾病进展，显著改善了运动活动，延长了生存期。我们首次报道了SOD1大鼠在脊髓运动神经元周围有异常无序的PNN结构，并且硫酸软骨素蛋白聚糖（CSPGs），如versican， aggrecan和phosphacan有不同的表达图谱，但没有连接蛋白-1。此外，SOD1大鼠具有不同的CSPG基因表达谱（Versican、Hapln1、Neurocan和Tenascin-R），而Aggrecan和Brevican基因表达谱保持不变。MSCs的应用保留了PNN的结构，同时运动神经元的存活率更高。我们检测了大鼠脑脊液中细胞因子（IL-1α、MCP-1、TNF-α、GM-CSF、IL-4、IFN-γ）的浓度，发现IL-1α和MCP-1的浓度显著升高。我们的研究结果表明，PNN和细胞因子稳态在SOD1大鼠ALS模型中发生了改变。这些变化有可能作为ALS的诊断、治疗效果评估和预后的生物学标志物。我们还表明，通过重塑受体的基因表达模式并具有神经保护和免疫调节作用，人类MSCs的管理是一种安全的程序，可以延迟运动功能的丧失并增加有症状的ALS动物的总体存活率。干细胞2014；32:3163 - 3172
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder resulting in a lethal outcome. We studied changes in ventral horn perineuronal nets (PNNs) of superoxide dismutase 1 (SOD1) rats during the normal disease course and after the intrathecal application (5 × 105 cells) of human bone marrow mesenchymal stromal cells (MSCs) postsymptom manifestation. We found that MSCs ameliorated disease progression, significantly improved motor activity, and prolonged survival. For the first time, we report that SOD1 rats have an abnormal disorganized PNN structure around the spinal motoneurons and give different expression profiles of chondroitin sulfate proteoglycans (CSPGs), such as versican, aggrecan, and phosphacan, but not link protein-1. Additionally, SOD1 rats had different profiles for CSPG gene expression (Versican, Hapln1, Neurocan, and Tenascin-R), whereas Aggrecan and Brevican profiles remained unchanged. The application of MSCs preserved PNN structure, accompanied by better survival of motorneurons. We measured the concentration of cytokines (IL-1α, MCP-1, TNF-α, GM-CSF, IL-4, and IFN-γ) in the rats' cerebrospinal fluid and found significantly higher concentrations of IL-1α and MCP-1. Our results show that PNN and cytokine homeostasis are altered in the SOD1 rat model of ALS. These changes could potentially serve as biological markers for the diagnosis, assessment of treatment efficacy, and prognosis of ALS. We also show that the administration of human MSCs is a safe procedure that delays the loss of motor function and increases the overall survival of symptomatic ALS animals, by remodeling the recipients' pattern of gene expression and having neuroprotective and immunomodulatory effects. Stem Cells 2014;32:3163–3172
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影响因子：
9.3
作者：
Fiala M;Chattopadhay M;La Cava A;Tse E;Liu G;Lourenco E;Eskin A;Liu PT;Magpantay L;Tse S;Mahanian M;Weitzman R;Tong J;Nguyen C;Cho T;Koo P;Sayre J;Martinez-Maza O;Rosenthal MJ;Wiedau-Pazos M
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通讯作者：
Sykova, Eva
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