Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1
Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1
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DOI：
10.1093/hmg/ddi446
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发表时间：
2006-01-15
影响因子：
3.5
通讯作者：
Comi, GP
中科院分区：
文献类型：
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作者：
Corti, S;Locatelli, F;Comi, GP
脊髓性肌萎缩伴呼吸窘迫1型（SMARD 1）是一种婴儿常染色体隐性运动神经元疾病，由免疫球蛋白mu结合蛋白2突变引起。我们研究了脊髓神经干细胞群的醛脱氢酶（ALDH）活性的基础上分离修改nmd小鼠，SMARD 1的动物模型的疾病进展的潜力。ALDH（hi）SSC（lo）干细胞具有自我更新和多能性，当鞘内移植到nmd小鼠体内时，会产生适当定位于脊髓腹角的运动神经元。移植的nmd动物表现出延缓疾病进展，保留运动神经元和腹根轴突，延长寿命。为了进一步研究导致这些差异的分子机制，我们对野生型、突变型和移植型nmd脊髓进行了微阵列和实时逆转录聚合酶链反应分析。我们证明了参与兴奋性氨基酸毒性和氧化应激处理的基因的下调，以及与野生型小鼠相比，nmd中染色质组织相关的基因的上调，这表明它们可能在SMARD 1发病机制中发挥作用。nmd移植小鼠的脊髓表达高水平的转录与神经发生相关的基因，如双皮质素（DCX），LIS1和dreplastin。成年nmd脊髓中存在DCX表达细胞表明外源性和内源性神经发生可能有助于观察到的nmd表型改善。
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal-recessive motor neuron disease caused by mutations in the immunoglobulin mu-binding protein 2. We investigated the potential of a spinal cord neural stem cell population isolated on the basis of aldehyde dehydrogenase (ALDH) activity to modify disease progression of nmd mice, an animal model of SMARD1. ALDH(hi)SSC(lo) stem cells are self-renewing and multipotent and when intrathecally transplanted in nmd mice generate motor neurons properly localized in the spinal cord ventral horns. Transplanted nmd animals presented delayed disease progression, sparing of motor neurons and ventral root axons and increased lifespan. To further investigate the molecular events responsible for these differences, microarray and real-time reverse transcription-polymerase chain reaction analyses of wild-type, mutated and transplanted nmd spinal cord were undertaken. We demonstrated a down-regulation of genes involved in excitatory amino acid toxicity and oxidative stress handling, as well as an up-regulation of genes related to the chromatin organization in nmd compared with wild-type mice, suggesting that they may play a role in SMARD1 pathogenesis. Spinal cord of nmd-transplanted mice expressed high transcript levels for genes related to neurogenesis such as doublecortin (DCX), LIS1 and drebrin. The presence of DCX-expressing cells in adult nmd spinal cord suggests that both exogenous and endogenous neurogeneses may contribute to the observed nmd phenotype amelioration.