Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation.
Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation.
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通过脊柱移植治疗肌萎缩侧索硬化症的人类神经干细胞替代疗法。
DOI：
10.1371/journal.pone.0042614
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Marsala M
中科院分区：
文献类型：
--
作者：
Hefferan MP;Galik J;Kakinohana O;Sekerkova G;Santucci C;Marsala S;Navarro R;Hruska-Plochan M;Johe K;Feldman E;Cleveland DW;Marsala M
普遍表达的细胞质超氧化物歧化酶（SOD1）突变导致遗传性肌萎缩性侧索硬化症（ALS）。运动神经元的突变合成驱动疾病发作和早期疾病进展。先前的实验研究表明，人胎儿脊髓神经干细胞（hNSCs）脊柱移植到SOD1G93A大鼠的腰椎脊髓中，可以获得适度的治疗效果，表现为局部α-运动神经元的保留和寿命的延长。本研究的目的是分析症状前免疫抑制SOD1G93A大鼠将hNSCs移植到腰椎前角后的治疗效果程度，并评估症状性SOD1G93A动物下行运动系统的存在和功能完整性。症状前SOD1G93A大鼠（60-65日龄）接受腰椎注射hNSCs。细胞移植后，分析疾病发生、疾病进展和寿命。在单独的SOD1G93A症状大鼠中，电刺激运动皮质后，通过脊髓表面记录电极分析下行运动束（皮质脊髓和红脊髓）的存在和功能电导率。采用银浸染腰椎脊髓切片和塑料脊髓切片的下行运动轴突计数，从形态学上验证下行运动束的完整性。将hNSCs移植到SOD1G93A大鼠腰椎后，对移植物细胞附近的α-运动神经元有保护作用，对移植物腰椎节段远处的α-运动神经元池无保护作用。对有症状的SOD1G93A大鼠胸椎脊髓的运动诱发电位分析显示，下行运动束传导几乎完全丧失，对应于大直径下行运动轴突的显著（50-65%）丧失。这些数据表明，为了实现更充分的临床治疗，细胞替代/基因治疗策略可能需要脊柱和脊柱上靶点。
Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1G93A rats leads to a moderate therapeutical effect as evidenced by local α-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1G93A rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1G93A animals. Presymptomatic SOD1G93A rats (60–65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1G93A rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal) was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1G93A rats protected α-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to α-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1G93A rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50–65%) loss of large caliber descending motor axons. These data demonstrate that in order to achieve a more clinically-adequate treatment, cell-replacement/gene therapy strategies will likely require both spinal and supraspinal targets.
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影响因子：
16.2
作者：
Kang, Shin H.;Fukaya, Masahiro;Yang, Jason K.;Rothstein, Jeffrey D.;Bergles, Dwight E.
通讯作者：
Bergles, Dwight E.
影响因子：
--
作者：
BRAAK, H;BRAAK, E;BOHL, J
通讯作者：
BOHL, J
影响因子：
2.9
作者：
DEOLMOS, JS;BELTRAMINO, CA;DELORENZO, SDO
通讯作者：
DELORENZO, SDO
影响因子：
19.7
作者：
Cosottini, M;Giannelli, M;Murri, L
通讯作者：
Murri, L
影响因子：
11
作者：
BROWNELL, B;OPPENHEIMER, DR;HUGHES, JT
通讯作者：
HUGHES, JT